Morpholinone and morpholine derivatives and uses thereof

ABSTRACT

This invention is directed to morpholinone and morpholine derivatives which are selective antagonists for human α 1a  receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia, sympathetic mediated pain, migraine, and for the treatment of any disease where the antagonism of the α 1a  receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

[0001] Throughout this application, various references are referred towithin parentheses. Disclosures of these publications in theirentireties are hereby incorporated by reference into this application tomore fully describe the state of the art to which this inventionpertains.

BACKGROUND OF THE INVENTION

[0002] The designation “α_(1a)” is the appellation recently approved bythe IUPHAR Nomenclature Committee for the previously designated “α_(1c)”cloned subtype as outlined in the Pharmacological Reviews (Hieble, etal. (1995) Pharmacological Reviews 47:267-270). The designation α_(1a)is used throughout this application and the supporting tables andfigures to refer to this receptor subtype. At the same time, thereceptor formerly designated α_(1a) was renamed α_(1d). The newnomenclature is used throughout this application. Stable cell linesexpressing these receptors are described herein; however, these celllines were deposited with the American Type Culture Collection (ATCC)under the old nomenclature (infra).

[0003] Benign Prostatic Hyperplasia (BPH), also called Benign ProstaticHypertrophy, is a progressive condition which is characterized by anodular enlargement of prostatic tissue resulting in obstruction of theurethra. This results in increased frequency of urination, nocturia, apoor urine stream, and hesitancy or delay in starting the urine flow.Chronic consequences of BPH can include hypertrophy of bladder smoothmuscle, a decompensated bladder, and an increased incidence of urinarytract infection. The specific biochemical, histological, andpharmacological properties of the prostate adenoma leading to thebladder outlet obstruction are not yet known. However, the developmentof BPH is considered to be an inescapable phenomenon for the aging malepopulation. BPH is observed in approximately 70% of males over the ageof 70. Currently, in the United States, the method of choice fortreating BPH is surgery (Lepor, H., Urol. Clinics North Amer., 17: 651,1990). Over 400,000 prostatectomies are performed annually (data from1986). The limitations of surgery for treating BPH include the morbidityrate of an operative procedure in elderly men, persistence or recurrenceof obstructive and irritative symptoms, as well as the significant costof surgery. A medicinal alternative to surgery is clearly verydesirable.

[0004] α-Adrenergic receptors (McGrath et al., Med. Res. Rev. 9:407-533, 1989) are specific neuroreceptor proteins located in theperipheral and central nervous systems on tissues and organs throughoutthe body. These receptors are important switches for controlling manyphysiological functions and, thus, represent important targets for drugdevelopment. In fact, many α-adrenergic drugs have been developed overthe past 40 years. Examples include clonidine, phenoxybenzamine andprazosin (for treatment of hypertension), naphazoline (a nasaldecongestant), and apraclonidine (for treatment of glaucoma).α-adrenergic drugs can be broken down into two distinct classes:agonists (e.g., clonidine and naphazoline), which mimic the receptoractivation properties of the endogenous neurotransmitter norepinephrine,and antagonists (e.g., phenoxybenzamine and prazosin), which act toblock the effects of norepinephrine. Many of these drugs are effective,but also produce unwanted side effects (e.g., clonidine produces drymouth and sedation in addition to its antihypertensive effects).

[0005] During the past 15 years, a more precise understanding ofα-adrenergic receptors and their drugs has evolved through increasedscientific scrutiny. Prior to 1977, only one (-adrenergic receptor wasknown to exist. Between 1977 and 1988, it was accepted by the scientificcommunity that at least two a-adrenergic receptors, α₁ and α₂, existedin the central and peripheral nervous systems. Since 1988, newtechniques in molecular biology have led to the identification of atleast six α-adrenergic receptors which exist throughout the central andperipheral nervous systems: α_(1a) (new nomenclature), α_(1b), α_(1d)(new nomenclature), α_(2a), α_(2b) and α_(2c) (Bylund, D. B., FASEB J.6: 832, 1992). In many cases, it is not known precisely whichphysiological responses in the body are controlled by each of thesereceptors. In addition, current α-adrenergic drugs are not selective forany particular α-adrenergic receptor. Many of these drugs produceuntoward side effects that may be attributed to their poor α-adrenergicreceptor selectivity.

[0006] Since the mid 1970's, nonselective α-antagonists have beenprescribed to treat BPH. In 1976, M. Caine et al. (Brit. J. Urol. 48:255, 1976) reported that the nonselective α-antagonist phenoxybenzaminewas useful in relieving the symptoms of BPH. This drug may produce itseffects by interacting with α-receptors located on the prostate.However, this drug also produces significant side effects such asdizziness and asthenia, which severely limit its use in treatingpatients on a chronic basis. More recently, the α-adrenergic antagonistsprazosin and terazosin have also been found to be useful for treatingBPH. However, these drugs also produce untoward side effects. It hasrecently been discovered that the α_(1a) receptor is responsible formediating the contraction of human prostate smooth muscle (Gluchowski,C. et al., WO 94/10989, 1994; Forray, C. et al., Mol. Pharmacol. 45:703, 1994). This discovery indicates that the ala antagonists may beeffective agents for the treatment of BPH with decreased side effects.Further studies have indicated that the ala receptor may also be presentin other lower urinary tract tissues, such as urethral smooth muscle(Ford et al., Br. J. Pharmacol. 114: 24P, 1995).

[0007] This invention is directed to morpholinone and morpholinederivatives which are selective antagonists for cloned human α_(1a)receptors. This invention is also related to uses of these compounds forlowering intraocular pressure (Zhan, et al., Ophthalmol. Vis. Sci. 34:Abst. #1133, 928, 1993), inhibiting cholesterol synthesis (D'Eletto andJavitt, J. Cardiovascular Pharmacol. 13: (Suppl. 2) S1-S4, 1989), benignprostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2,1991), sympathetically mediated pain (Campbell, WO 92/14453, 1992),cardiac arrhythmia (Spiers, et al., J. Cardiovascular Pharmacol. 16:824-830, 1990), migraine (K. A. Vatz, Headache 37: 107-108, 1997) andfor the treatment of any disease where antagonism of the α_(1a) receptormay be useful.

SUMMARY OF THE INVENTION

[0008] This invention is directed to a compound having the structure:

[0009] where W is O, S, or NR₈; wherein R₈ is independently H, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

[0010] where Y is independently O or S;

[0011] where R₂ is aryl or heteroaryl; wherein the aryl or heteroarylmay be substituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n) YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; and wherein n independently is an integer from 0to 7 inclusive;

[0012] where R₃ is independently H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, or polyfluoroalkyl;

[0013] where R₄ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,—C(Y)R₈, —C(Y)N(R₈)₂, —C₂R₈, straight chained or branched C₁-C₇ alkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl,C₅-C₇ cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzylmay be substituted with one or more of F; Cl; Br; I; —CN; —NC₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; (CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(RB)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; and wherein t independently is an integer from 1to 4 inclusive;

[0014] where R₅ is H, (CH₂)_(t)YRB, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, orphenyl or benzyl; wherein the phenyl or benzyl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂, —SO₂R₈; —(CH₂) C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,or carboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

[0015] where R₆ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,—C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straight chained or branched C₁-C₇ alkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl,C₅-C₇ cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzylmay be substituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; where R₇ is H, —(CH₂)_(t)YR8, —(CH₂)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, orphenyl or benzyl; wherein the phenyl or benzyl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂) YR₈; —(CH₂) C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl;

[0016] where q is an integer from 0 to 4 inclusive;

[0017] where each R₈, n, and t independently is as defined above;

[0018] where R, is

[0019] wherein each R₉ is H; straight chained or branched C₁-C₇ alkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C₅-C₇cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl maybe substituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)CO₂R₈; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; orC₅-C₇ cycloalkenyl;

[0020] wherein each R₁₀ is H; F; —OH; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; aryl orheteroaryl; straight chained or branched C₁-C₇ alkyl, hydroxyalkyl,aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; orC₅-C₇ cycloalkenyl; wherein the alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl may be substituted with one or more aryl or heteroaryl;wherein the aryl or heteroaryl may be substituted with one or more of F;Cl; Br; I; —(CH₂),YR₈; —(CH₂)C(Y)R₈; —(CH₂)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N (R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl, orpolyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;

[0021] wherein each R₁₁ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y) R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

[0022] wherein each R₁₂ is independently H —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl; wherein R₁₃ is H, C₁-C₇ alkyl,—C(O)R₂, aryl, heteroaryl, C₁-C₇ alkyl substituted with one or two aryl,or C₁-C₇ alkyl substituted with one or two heteroaryl; wherein the arylor heteroaryl may be substituted with one or more of F; Cl; Br; I; —CN;—NO₂; —N(R₈)₂; —S0₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ aminoalkyl, alkenyl, or alkynyl;C₃-C₇ cycloalkyl; or C₁-C₇ cycloalkenyl;

[0023] wherein R₁₄ is H, straight chained or branched C₁-C₇ akyl;

[0024] wherein Z is O, S, NR₁₄, CO, CH₂,

[0025] wherein Y₁, Y₂, and Y₃ independently are H; F; Cl; Br; I; —CN;—NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂),YR₈; —(CH₂)C(Y)N(R₈)₂;—(CH₂)CO₂R₈; straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl;

[0026] wherein each m is independently 1 or 2;

[0027] wherein each p is independently an integer from 0 to 2 inclusive;

[0028] wherein J is

[0029] or C₂-C₇ alkenyl;

[0030] wherein each R₁₅ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

[0031] wherein each R₁₆ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(Ra)₂ —(CH₂)C(Y) R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)N(R₈)₂,—(CH₂)_(t)CN, straight chained or branched C₁-C₇ alkyl, straight chainedor branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇cycloalkenyl;

[0032] wherein each R₁₇ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; —C(Y)R₈; —C(Y)N(R₈)₂; —CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl,aminoalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

[0033] wherein each R₁₈ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y) R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

[0034] wherein L is S, O, or N(R₈);

[0035] wherein u is an integer from 0 to 1 inclusive;

[0036] or a pharmaceutically acceptable salt thereof.

[0037] This invention provides for a pharmaceutical compositioncomprising a therapeutically effective amount of any one of thecompounds described herein and a pharmaceutically acceptable carrier.

[0038] This invention provides for a method of treating a subjectsuffering from benign prostatic hyperplasia which comprisesadministering to the subject an amount of any one of the compoundsdescribed herein effective to treat benign prostatic hyperplasia.

[0039] This invention provides for a method of treating a subjectsuffering from high intraocular pressure which comprises administeringto the subject an amount of any one of the compounds described hereineffective to lower intraocular pressure.

[0040] This invention provides for a method of treating a subjectsuffering from a disorder associated with high cholesterol whichcomprises administering to the subject an amount of any one of thecompounds described herein effective to inhibit cholesterol synthesis.

[0041] This invention provides for a method of treating a subjectsuffering from cardiac arrhythmia which comprises administering to thesubject an amount of any one of the compounds described herein effectiveto treat cardiac arrhythmia.

[0042] This invention provides for a method of treating a subjectsuffering from impotency which comprises administering to the subject anamount of any one of the compounds described herein effective to treatimpotency.

[0043] This invention provides for a method of treating a subjectsuffering from sympathetically mediated pain which comprisesadministering to the subject an amount of any one of the compoundsdescribed herein effective to treat sympathetically mediated pain.

[0044] This invention provides for a method of treating a subjectsuffering from migraine which comprises administering to the subject anamount of any one of the compounds described herein effective to treatmigraine.

[0045] This invention provides for a method of treating a disease whichis susceptible to treatment by antagonism of the α_(1a) receptor whichcomprises administering to the subject an amount of any one of thecompounds described herein effective to treat the disease.

[0046] This invention provides for a method of treating a subjectsuffering from benign prostatic hyperplasia which comprisesadministering to the subject an amount of any one of the compoundsdescribed herein in combination with a 5-alpha reductase inhibitoreffective to treat benign prostatic hyperplasia.

[0047] This invention provides for a pharmaceutical compositioncomprising a therapeutically effective amount of any one of thecompounds described herein in combination with a therapeuticallyeffective amount of finasteride and a pharmaceutically acceptablecarrier.

[0048] This invention provides for a method of relaxing lower urinarytract tissue which comprises contacting the lower urinary tract tissuewith an amount of any one of the compounds described herein effective torelax lower urinary tract tissue.

[0049] This invention provides for a method of relaxing lower urinarytract tissue in a subject which comprises administering to the subjectan amount of any one of the compounds described herein effective torelax lower urinary tract tissue.

[0050] This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein and a pharmaceutically acceptable carrier.

[0051] This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein with a therapeutically effective amount of finasterideand a pharmaceutically acceptable carrier.

[0052] This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein and a pharmaceuticallyacceptable carrier.

[0053] This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein with a therapeuticallyeffective amount of finasteride and a pharmaceutically acceptablecarrier.

BRIEF DESCRIPTION OF THE FIGURES

[0054] FIGS. 1A-1F

[0055] FIGS. 1A-1F show the structures of the compounds described hereinin the Examples.

DETAILED DESCRIPTION OF THE INVENTION

[0056] This invention provides for a compound having the structure:

[0057] where W is O, S, or NR₈; wherein R₈ is independently H, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₁-C₇ cycloalkenyl;

[0058] where Y is independently O or S;

[0059] where R₂ is aryl or heteroaryl; wherein the aryl or heteroarylmay be substituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(RB)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₆; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; and wherein n independently is an integer from 0to 7 inclusive;

[0060] where R₃ is independently H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, or polyfluoroalkyl;

[0061] where R₄ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,—C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straight chained or branched C₁-C₇ alkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl,C₅-C₇ cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzylmay be substituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₉; —(CH₂)C(Y)R₈; —(CH₂)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)CO₂R₆;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl; and wherein t independently is an integer from 1 to 4inclusive;

[0062] where R₅ is H, —(CH₂)_(t)YR₈ —(CH₂)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl or benzyl;wherein the phenyl or benzyl may be substituted with one or more of F;Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

[0063] where R₆ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)N(R)₂, —(CH₂)_(t)CN, —C(Y)R₈,—C(Y)N(R₈)₂, —CO₂R₈, straight chained or branched C₁-C₇ alkyl, straightchained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzyl may besubstituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y) R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl;

[0064] where R₇ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, orphenyl or benzyl; wherein the phenyl or benzyl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl;

[0065] where q is an integer from 0 to 4 inclusive;

[0066] where each R₈, n, and t independently is as defined above;

[0067] where R₁ is

[0068] wherein each R₉ is H; straight chained or branched C₁-C₇ alkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C₅-C₇cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl maybe substituted with one or more of F; Cl; Br; I; —(CH₂)YR₈;—(CH₂)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)CO₂R₈; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; orC₅-C₇ cycloalkenyl;

[0069] wherein each R₁₀ is H; F; —OH; —(CH₂)_(n)C(Y)R₆; —(CH₂)_(n)YR₈;—(CH₂)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; aryl orheteroaryl; straight chained or branched C₁-C₇ alkyl, hydroxyalkyl,aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; orC₅-C₇ cycloalkenyl; wherein the alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl may be substituted with one or more aryl or heteroaryl;wherein the aryl or heteroaryl may be substituted with one or more of F;Cl; Br; I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl; straightchained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, or polyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;

[0070] wherein each R₁₁ is independently H, —(CH₂)_(t)YR₈,—(CH₂)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)C₂R₈, —(CH₂)_(t)N (R₈)₂,—(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straight chained or branchedC₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl,C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

[0071] wherein each R₁₂ is independently H, —(CH₂)_(t)YR₈,—(CH₂)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂,—(CH₂)_(t)CN, straight chained or branched C₁-C₇ alkyl, straight chainedor branched C₂-C, alkenyl or alkynyl, C₃-C₇ cycloalkyl or C₅-C₇cycloalkenyl; wherein R₁₃ is H, C₁-C₇ alkyl, —C(O)R₂, aryl, heteroaryl,C₁-C₇ alkyl substituted with one or two aryl, or C₁-C₇ alkyl substitutedwith one or two heteroaryl; wherein the aryl or heteroaryl may besubstituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl; straight chainedor branched C₂-C₇ aminoalkyl, alkenyl, or alkynyl; C₃-C₇ cycloalkyl; orC₁-C₇ cycloalkenyl;

[0072] wherein R₁₄ is H, straight chained or branched C₁-C₇ akyl;

[0073] wherein Z is O, S, NR₁₄, CO, CH₂,

[0074] wherein Y₁, Y₂, and Y₃ independently are H; F; Cl; Br; I; —CN;—NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

[0075] wherein each m is independently 1 or 2;

[0076] wherein each p is independently an integer from 0 to 2 inclusive;

[0077] wherein J is

[0078] or C₂-C₇ alkenyl;

[0079] wherein each R₁₅ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

[0080] wherein each R₁₆ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl, or C₅-C₇ cycloalkenyl;

[0081] wherein each R₁₇ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; —C(Y)R₈; —C(Y)N(R₈)₂; —CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl,aminoalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

[0082] wherein each R₁₈ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈; —(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl;

[0083] wherein L is S, O, or N(R₈);

[0084] wherein u is an integer from 0 to 1 inclusive;

[0085] or a pharmaceutically acceptable salt thereof.

[0086] The invention also provides for the (−) and (+) enantiomers ofall compounds of the subject application described herein.

[0087] The invention further provides for the cis and trans enantiomersof all of the compounds of the subject application described herein. Itis noted herein that the terms “cis” and “trans” correspond to relativestereochemistry, as determined, for example, by NOE (Nuclear OverhauserEffect) experiments.

[0088] The compounds of the present invention are preferably at least80% pure, more preferably at least 90% pure, and most preferably atleast 95% pure.

[0089] In the present invention, the term “aryl” is used to includephenyl, benzyl, benzoyl, or naphthyl; and the term “heteroaryl” is usedto include pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyridyl,imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl,benzfurazanyl, benzfuranyl,or quinolyl.

[0090] The compounds of this invention exhibit greater affinity,preferably at least ten-fold greater affinity, for the human alareceptor over the human α_(1b) or human α_(1d) receptors.

[0091] In one embodiment, W is O.

[0092] In another embodiment, J is

[0093] In another embodiment, R₁ is

[0094] In another embodiment, R₉ is aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; and R₁₀ is H; —CN; —OH; —CO₂R₈;aryl or heteroaryl; wherein the aryl or heteroaryl may be substitutedwith one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, orpolyfluoroalkyl.

[0095] In another embodiment of the invention, the compound has thestructure:

[0096] wherein R₂ is phenyl; wherein the phenyl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl.

[0097] In another embodiment, J is

[0098] In another embodiment, R₁ is

[0099] In another embodiment, R₉ is phenyl or pyridyl, wherein thephenyl or pyridyl may be substituted with one or more of F; Cl; Br; I;—(OH₂)_(n)YR₈; (OH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl;

[0100] R₁₀ is H, —CN, —OH, —CO₂R₈, or phenyl; wherein the phenyl may besubstituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈, —CN; —NO₂; —N(R₈)₂;—SO₂R₆; straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, orpolyfluoroalkyl; and

[0101] R₁₃ is phenyl; wherein the phenyl may be substituted with one ormore of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ aminoalkyl,alkenyl, or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl.

[0102] In another preferred embodiment, the R₄ is H, alkyl, cycloalkyl,—CO₂R₃, or —C(Y)N(R₃)₂; and R₁₀ is H, F, C₁-C₇ alkyl, C₁-C₇ alkoxy, orOH.

[0103] The invention provides for a pharmaceutical compositioncomprising a therapeutically effective amount of any of the compoundsdescribed above and a pharmaceutically acceptable carrier. In thesubject invention, a “therapeutically effective amount” is any amount ofa compound which, when administered to a subject suffering from adisease against which the compounds are effective, causes reduction,remission, or regression of the disease.

[0104] In one embodiment, the therapeutically effective amount is anamount from about 0.01 mg per subject per day to about 800 mg persubject per day, preferably from about 0.01 mg per subject per day toabout 500 mg per subject per day, more preferably from about 0.01 mg persubject per day to about 250 mg per subject per day, more preferablyfrom about 0.1 mg per subject per day to about 60 mg per subject per dayand most preferably from about 1 mg per subject per day to about 20 mgper subject per day. In the practice of this invention, the“pharmaceutically acceptable carrier” is any physiological carrier knownto those of ordinary skill in the art useful in formulatingpharmaceutical compositions.

[0105] In one embodiment the pharmaceutical carrier may be a liquid andthe pharmaceutical composition would be in the form of a solution. Inanother embodiment, the pharmaceutically acceptable carrier is a solidand the composition is in the form of a powder or tablet. In a furtherembodiment, the pharmaceutical carrier is a gel and the composition isin the form of a suppository or cream. In a further embodiment thecompound may be formulated as a part of a pharmaceutically acceptabletransdermal patch.

[0106] A solid carrier can include one or more substances which may alsoact as flavoring agents, lubricants, solubilizers, suspending agents,fillers, glidants, compression aids, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders, thecarrier is a finely divided solid which is in admixture with the finelydivided active ingredient. In tablets, the active ingredient is mixedwith a carrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

[0107] Liquid carriers are used in preparing solutions, suspensions,emulsions, syrups, elixirs and pressurized compositions. The activeingredient can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, a mixtureof both or pharmaceutically acceptable oils or fats. The liquid carriercan contain other suitable pharmaceutical additives such assolubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoringagents, suspending agents, thickening agents, colors, viscosityregulators, stabilizers or osmo-regulators. Suitable examples of liquidcarriers for oral and parenteral administration include water (partiallycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

[0108] Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Carriers are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings.

[0109] The compound can be administered orally in the form of a sterilesolution or suspension containing other solutes or suspending agents,for example, enough saline or glucose to make the solution isotonic,bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleateesters of sorbitol and its anhydrides copolymerized with ethylene oxide)and the like.

[0110] The compound can also be administered orally either in liquid orsolid composition form. Compositions suitable for oral administrationinclude solid forms, such as pills, capsules, granules, tablets, andpowders, and liquid forms, such as solutions, syrups, elixirs, andsuspensions. Forms useful for parenteral administration include sterilesolutions, emulsions, and suspensions.

[0111] Optimal dosages to be administered may be determined by thoseskilled in the art, and will vary with the particular compound in use,the strength of the preparation, the mode of administration, and theadvancement of the disease condition. Additional factors depending onthe particular subject being treated will result in a need to adjustdosages, including subject age, weight, gender, diet, and time ofadministration.

[0112] In another embodiment, any one of the compounds described hereinadditionally does not cause a fall in blood pressure at dosageseffective to alleviate benign prostatic hyperplasia.

[0113] The invention provides a method of treating a subject sufferingfrom benign prostatic hyperplasia, which comprises administering to thesubject any one of the compounds described herein effective to treatbenign prostatic hyperplasia. In a preferred embodiment, the compound ofthe pharmaceutical composition additionally does not cause a fall inblood pressure at dosages effective to alleviate benign prostatichyperplasia. In a preferred embodiment, the compound effects treatmentof benign prostatic hyperplasia by relaxing lower urinary tract tissueand in particular where lower urinary tract tissue is prostatic smoothmuscle.

[0114] In the practice of this invention, the term “lower urinary tracttissue” is used to include prostatic capsule, prostate urethra, urethralsmooth muscle, prostatic smooth muscle, and bladderneck.

[0115] The invention further provides a method of treating a subjectsuffering from elevated intraocular pressure, which comprisesadministering to the subject one of the compounds described hereineffective to lower intraocular pressure.

[0116] The invention further provides a method of treating a subjectsuffering from a disorder associated with elevated blood cholesterol,which comprises administering to the subject one of the compoundsdescribed herein effective to inhibit cholesterol synthesis.

[0117] The invention provides a method of treating a subject sufferingfrom cardiac arrhythmia, which comprises administering to the subjectone of the compounds described herein effective to treat cardiacarrhythmia.

[0118] The invention further provides a method of treating a subjectsuffering from impotency, which comprises administering to the subjectone of the compounds described herein effective to treat impotency.

[0119] The invention further provides a method of treating a subjectsuffering from sympathetically mediated pain, which comprisesadministering to the subject one of the compounds described hereineffective to treat sympathetically mediated pain.

[0120] This invention provides a method of treating a subject sufferingfrom migraine which comprises administering to the subject one of thecompounds described herein effective to treat migraine.

[0121] The invention also provides a method of treating a disease whichis susceptible to treatment by antagonism of the α_(1a) receptor, whichcomprises administering to the subject one of the compounds describedherein effective to treat the disease.

[0122] The invention provides a method of treating a subject sufferingfrom benign prostatic hyperplasia, which comprises administering to thesubject one of the compounds described herein in combination with a5-alpha reductase inhibitor effective to treat benign prostatichyperplasia. In one preferred embodiment the 5-alpha reductase inhibitoris finasteride.

[0123] This invention provides for a pharmaceutical compositioncomprising a therapeutically effective amount of any one of the compounddescribed herein in combination with a therapeutically effective amountof finasteride and a pharmaceutically acceptable carrier. This inventionalso provides for a pharmaceutical composition comprising any one of thecompounds described herein present in an amount from about 0.01 mg toabout 800 mg and the therapeutically effective amount of the finasterideis about 5 mg. In one embodiment, the pharmaceutical composition is anyone of the compounds described herein present in an amount from about0.1 mg to about 60 mg and the therapeutically effective amount offinasteride is about 5 mg. In another embodiment, the pharmaceuticalcomposition is any one of the compounds described herein present in anamount from about I mg to about 20 mg and the therapeutically effectiveamount of finasteride is about 5 mg.

[0124] The invention further provides a method of relaxing lower urinarytract tissue which comprises contacting the lower urinary tract tissuewith an amount of one of the compounds described herein effective torelax lower urinary tract tissue. In one embodiment the lower urinarytract tissue is prostatic smooth muscle. In one preferred embodiment,the compound additionally does not cause a fall in blood pressure whenit is effective to relax lower urinary tract tissue.

[0125] The invention provides a method of relaxing lower urinary tracttissue in a subject which comprises administering to the subject anamount of one of the compounds described herein effective to relax lowerurinary tract tissue. In one embodiment the lower urinary tract tissueis prostatic smooth muscle. In one preferred embodiment, the compoundadditionally does not cause a fall in blood pressure when it iseffective to relax lower urinary tract tissue.

[0126] This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein and a pharmaceutically acceptable carrier.

[0127] This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein with a therapeutically effective amount of finasterideand a pharmaceutically acceptable carrier.

[0128] This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein and a pharmaceuticallyacceptable carrier.

[0129] This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein with a therapeuticallyeffective amount of finasteride and a pharmaceutically acceptablecarrier.

[0130] Included in this invention are pharmaceutically acceptable saltsand complexes of all of the compounds described herein. The saltsinclude but are not limited to the following acids and bases: inorganicacids which include hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, and boric acid; organic acids which include aceticacid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, maleic acid, citric acid, methanesulfonic acid, benzoic acid,glycolic acid, lactic acid, and mandelic acid; inorganic bases whichinclude ammonia; and organic bases which include methylamine,ethylamine, hydroxyethylamine, propylamine, dimethylamine, diethylamine,trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine,morpholine, piperazine, and guanidine. This invention further providesfor the hydrates and polymorphs of all of the compounds describedherein.

[0131] The present invention includes within its scope prodrugs of thecompounds of this inventions. In general, such prodrugs will befunctional derivatives of the compounds of the invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in Design of Prodrugs, ed. H. Bundgaard,Elsevier, 1985.

[0132] The present invention further includes metabolites of thecompounds of the present invention. Metabolites include active speciesproduced upon introduction of compounds of this invention into thebiological milieu.

[0133] One skilled in the art will readily appreciate that appropriatebiological assays will be used to determine the therapeutic potential ofthe claimed compounds for the treating the above noted disorders.

[0134] This invention will be better understood from the ExperimentalDetails which follow. However, one skilled in the art will readilyappreciate that the specific methods and results discussed are merelyillustrative of the invention as described more fully in the claimswhich follow thereafter.

[0135] Experimental Details

[0136] I. Synthesis of Morpholinone Examples (Schemes 1 and 2):

[0137] 1. Synthesis of3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenylester (Scheme 1)

[0138] a. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone

[0139] To a solution of KOH (56 g, 1.0 mol) in MeOH (500 mL) was added3,4-difluoroacetophenone (15.6 g, 0.1 mol) dropwise over 15 min at 0° C.Phenyliodosodiacetate (64.4 g, 0.2 mol) was added in small portions overa 20 min period, and the resulting yellow-orange solution was stirredovernight at room temperature. The solvent was removed in vacuo toobtain a yellow-orange gum. The residue was dissolved in 100 mL of waterand 100 mL of brine and was thoroughly extracted with ethyl acetate(3×150 mL). The organic layer was dried over Na₂SO₄ and was decanted.The solvent was removed in vacuo to obtain 31.0 g of the acetal as thickyellow oil. It was dissolved in 200 mL of acetone and about 10 drops ofconcentrated sulfuric acid. The reaction mixture was stirred at roomtemperature for 2 hours until TLC analysis showed complete consumptionof the starting material. The solvent was removed in vacuo and the solidthat was obtained was first basified by adding saturated NaHCO₃ solutionand then it was extracted with ethyl acetate (300 mL). The organic layerwas separated and washed with brine. The organic layer was dried overMgSO₄, filtered, and the solvent was removed in vacuo to obtain a yellowsolid. The yellow solid was washed with cold hexane (to removeiodobenzene impurities) and dried to obtain 11.4 g (66% yield) of1-hydroxy-(3,4-difluorophenyl)-acetophenone as pale yellow solid. Theproduct was shown to be >90% pure by NMR and was used in the next stepwithout further purification.

[0140] b. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone oxime

[0141] To a solution of 1-hydroxy-(3,4-difluorophenyl)-acetophenone (6.0g, 34.9 mmol) in 150 mL of MeOH was added hydroxylamine hydrochloride(3.16 g, 45.6 mmol) and sodium acetate (9.6 g, 69.6 mmol) at roomtemperature and the resulting solution was stirred overnight. Thesolvent was removed and the residue was dissolved in methylene chloride(150 mL) and was washed with 100 mL of saturated NaHCO₃ solutionfollowed by brine. The organic layer was separated and dried over MgSO₄₁filtered, and the solvent was removed in vacuo to obtain1-hydroxy-(3,4-difluorophenyl)-acetophenone-oxime as a yellow solid (5.6g, 86%). It was used in the next step without any purification.

[0142] c. 2-Amino-2-(3,4-difluorophenyl)-ethanol

[0143] To a well stirred suspension of LiAlH₄ (3.4 g, 89.5 mmol) in THF(120 mL) in a 3-necked round bottom flask fitted with a condenser and adropping funnel was added a solution of1-hydroxy-(3,4-difluorophenyl)-acetophenone-oxime (4.6 g, 24.6 mmol) inTHF (50 mL) dropwise at 0° C. The resulting greyish yellow suspensionwas heated to reflux for 2 hours. The reaction mixture was cooled to 0°C. and then carefully quenched sequentially with 3.4 mL of water, 3.4 mLof 3N NaOH, and 10 mL of water. The resulting suspension was filteredthrough a fritted glass funnel. To the residue was added 100 mL Et₂O andthe suspension was heated to reflux for 20 min. The suspension wasfiltered and was combined with the previous filtrate, dried over MgSO₄,filtered, and the solvent was removed in vacuo.2-Amino-2-(3,4-difluorophenyl)-ethanol was obtained as a yellow glassysyrup (4.1 g, 96%) which was used in the next step without furtherpurification. Method A for the synthesis of5-(3,4-difluoro-phenyl)-morpholin-3-one:

[0144] d. 2-Chloro—N-[1-(3,4-difluoro-phenyl)-2-hydroxyethyl]-acetamide

[0145] To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol 2.6 g,15.0 mmol) in CH₂Cl₂ (15 mL) and 20% (by wt.) NaOH (15 mL) was added asolution of chloroacetyl chloride (1.32 mL, 16.5 mmol) in 15 mL ofCH₂Cl₂ at −10° C. dropwise under argon atmosphere. After the additionwas complete, the reaction mixture was stirred for 15 min and then itwas transferred to a separatory funnel. The organic layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (2×20 mL). The combinedorganic extracts were washed with a solution containing 10 mL of brineand 5 drops of concentrated HCl. The organic layer was dried over MgSO₄,filtered and the solvent was removed in vacuo to give a white solid. Itwas further purified with flash column chromatography on silica gel with1:1 hexane/EtOAc followed by EtOAc as the eluting system.2-Chloro—N-[l-(3,4-difluorophenyl)-2-hydroxy-ethyl]-acetamide wasobtained as a white solid (2.6 g, 69.5% yield).

[0146] e. 5-(3,4-Difluoro-phenyl)-morpholin-3-one

[0147] To a suspension of sodium hydride (0.29 g, 11.39 mmol) in 48 mLTHF was added a solution of2-chloro—N-[1-(3,4-difluoro-phenyl)-2-hydroxy-ethyl]-acetamide (2.6 g,10.4 mmol) in 48 mL THF dropwise via a dropping funnel at −25° C. over20 min. After the addition was over, the cooling bath was removed andthe reaction mixture was stirred at room temperature for 8 hours. TLCanalysis indicated a complete disappearance of the starting material.The reaction was quenched by adding a few crystals of ice. It wasextracted thoroughly with EtOAc (3×30 mL) and was washed with brine. Theorganic layer was separated and dried over MgSO₄. The organic layer wasfiltered and the solvent was removed in vacuo. The residue was suspendedin EtOAc and the white solid was collected via filtration which wasfound to be 5-(3,4-difluoro-phenyl)-morpholin-3-one (0.8 g, 38% yield).

[0148] Method B for the synthesis of5-(3,4-difluoro-phenyl)-morpholin-3-one:

[0149] f. 5-(3,4-difluoro-phenyl)-morpholin-3-one

[0150] To a suspension of NaH (8.0 mmol, 0.19 g) in 10 mL THF at 0° C.was added a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (7.51mmol, 1.3 g) in 20 mL THF dropwise via an addition funnel and after 30min ethyl chloroacetate was added dropwise via syringe. The orangecolored reaction mixture was stirred for 2 hours at 0° C. and then for 2hours at 35° C. The solvent was removed and the5-(3,4-difluoro-phenyl)-morpholin-3-one was isolated as a thick yellowoil (0.5 g). ¹H NMR showed that the product was about 85% pure and anyattempts to purify it further by column chromatography were notsuccessful. It was used in the next reaction as described below withoutfurther purification.

[0151] g. 3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester

[0152] To a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (0.34 g,1.57 mmol) in 10 mL of THF was added NaH (0.05 g, 1.9 mmol) and theresulting solution was stirred for 30 min. It was then transferred via asyringe into a solution of 4-nitrophenyl chloroformate in 20 mL ofanhydrous THF at −78° C. under argon. The resulting solution was stirredfor 2 hours after which the solvent was removed and the residue waspurified by column chromatography on silica gel with 1:1 hexane/CH₂Cl₂followed by CH₂Cl₂ to obtain3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenylester as a colorless thick oil (0.31 g, 51%).

[0153] 2. Synthesis of(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (Scheme 2)

[0154] a.[l-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamicacid-tert-butyl ester

[0155] To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (8.6 g,49.7 mmol) in CHCl₃ (150 mL) at 0° C. was added a solution ofdi-tert-butyl dicarbonate (11.4 g, 52.0 mmol) in CHCl₃ (50 mL) in oneportion and the resulting solution was stirred overnight at roomtemperature. The solvent was removed in vacuo and the residue wassubjected to column chromatography on silica gel (2:1 hexane-EtOAcfollowed by EtOAc) to obtain[1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl esteras white solid (10.0 g, 74%).

[0156] b. (+)-4-(3,4-Difluorophenyl)-oxazolidin-2-one

[0157] To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40mL) at room temperature was added a solution of[1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester(5.0 g, 18.3 mmol) in 20 mL THF via a dropping funnel at roomtemperature. The resulting suspension was stirred for 3 hours and thenquenched carefully with 10 mL of water. The biphasic mixture wasextracted with 100 mL of Et₂O, washed with brine, filtered, and thesolvent was removed in vacuo. The gummy residue thus obtained waspurified by column chromatography over silica gel (R_(f)=0.15, 3:2hexane-EtOAc) to obtain 4-(3,4-difluorophenyl)-oxazolidin-2-one as awhite flaky solid (2.8 g, 77%). M.P. 81°-83° C.; ¹H NMR δ 4.13 (dd,J=6.6 Hz, J=8.7 Hz, 1 H), 4.73 (t, J=8.7 Hz, 1 H), 4.94 (dd, J=6.6 Hz,J=8.7 Hz, 1 H) , 6.08 (br, s, 1 H), 7.03-7.23 (m, 3 H) . The enantiomerswere separated by using Chiralcel OD column (4.6×250 mm) using 80%hexane/20% isopropyl alcohol/0.1% diethylamine as the eluting systemunder isothermal conditions (U.V. 254 nM). The retention times for thetwo isomers were 16.19 min and 20.08 min respectively. First isomer:[α]D=+62.9 (c=0.67, acetone); Analysis calculated for C₉H₇NO₂F₂: C,54.28; H, 3.54; N, 7.03. Found: C, 54.16; H, 3.44; N, 6.96. Secondisomer: [α]_(D)=−56.9 (c=0.75, acetone); Analysis calculated forC₉H₇NO₂F₂: C, 54.28; H, 3.54; N, 7.03. Found: C, 54.31; H, 3.46; N,6.98. The first isomer was used in the next step.

[0158] c. (+)-2-Amino-2-(3,4-difluorophenyl)-ethanol

[0159] To a solution of (+)-4- (3,4-difluorophenyl)-oxazolidin-2-one(1.39 mmol, 0.27 g) in 5.0 mL ethanol was added 5.0 mL of water andpellets of potassium hydroxide (5.0 mmol, 0.28 g). The resultingsolution was then heated to reflux overnight. The solvent was removed invacuo and the resulting residue was extracted with EtOAc (2×50 mL). Theorganic extracts were washed with brine and the organic layer was driedover Na₂SO₄. It was filtered and the solvent was removed in vacuo toobtain (+)-2-amino-2-(3,4-difluorophenyl)-ethanol as a white solid (0.21g, 87% yield).

[0160] This material was converted into(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester in the same manner as described in section Ipart 1 g.

[0161] 3. Typical reaction for the coupling of side chains (RNH₂) withactivated morpholinones (Schemes 1 and 2). Synthesis of(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-amide(Compound 1)

[0162] a. 4-(5-Fluoro-2-methoxy)-phenyl-4-phenyl-piperidinehydrochloride

[0163] To a 100 mL round bottom flask equipped with a rubber septum anda stirring bar was added 4-hydroxy-4-phenyl-piperidine (1.25 g, 7.0mmol) followed by 10 mL of 4-fluoroanisole. The resulting solution wasstirred at room temperature under argon atmosphere and AlCl₃ (2.82 g,21.0 mmol) was added in one portion. An exotherm was observed. Thereaction mixture was stirred for 8 hours and then poured carefully over150 ml of ice-water. The white solid that precipitated out was filteredand washed thoroughly with water followed by diethyl ether to obtain4-(5-fluoro-2-methoxy)-phenyl-4-phenyl-piperidine hydrochloride (1.59 g,50%) as a white solid.

[0164] b.3-[4-(2-methoxy-5-fluoro)phenyl-4-phenyl-piperidin-1-yl]propylamine

[0165] To a solution of4-(5-fluoro-2-methoxy)-phenyl-4-phenyl-piperidine (0.6 g, 2.1 mmol) in30 mL dioxane was added 3-bromo—N-tert-butoxycarbonyl-propylamine (0.6g, 2.5 mmol) and K₂CO₃ (0.6 g, 6.0 mmol) and the resulting suspensionwas heated to reflux for 10 hours. The suspension was allowed to cool,filtered, and the solvent was evaporated to obtain yellow residue whichwas purified by column chromatography (Rf=0.4, 3:1 EtOAc/MeOH) to obtain3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]—N-tert-butoxycarbonyl-propylamineas a yellow oil (0.35 g). This was dissolved in 15 mL of CH₂Cl₂ and 3.0mL of trifluoroacetic acid was added with stirring at room temperatureunder argon atmosphere for 1 hour. The solvent was evaporated in vacuoand the residue was basified to pH 10 by adding minimum amount of 1 NKOH solution. The product was extracted with CH₂Cl₂ (3×25 mL), driedover MgSO₄, filtered, and the solvent was removed in vacuo to obtain3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]propylamine as ayellow oil (0.25 g, 35% for two steps). It was used in the next stepwithout further purification.

[0166] c. (+)-3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-amide(Compound 1)

[0167] To a solution of (+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenylester (0.05 g, 0.13 mmol) in 5 mL THF was added3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl)-propylamine(0.06g) in one portion and the resulting mixture was stirred at roomtemperature overnight. The solvent was removed in vacuo and the residuewas passed through a short silica gel column with 1: hexane/EtOAcfollowed by 10% MeOH/EtOAc as the eluting system.3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-amidewas obtained as a colorless oil (0.05 g) . It was dissolved in 4 mL ofCHCl₃ and then treated with 1 mL of 1N HCl in diethyl ether to obtainits HCl salt. White solid. M.P.=110°-113° C.; [α]D=+25.3 (c=0.14, MeOH); Analysis calculated for C₃₂H₃₅N₃O₄F₃Cl.1.1 CHCl₃: C, 53.05; H, 4.86;N, 5.61. Found: C, 53.24; H, 5.06; N, 5.44.

[0168] 4. Morpholinone example: the synthesis of(+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide(Compound 2)

[0169] a. 1-Benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol

[0170] To a cooled solution of n-BuLi (6.0 mL, 15.0 mmol) in 20 mL THFwas added 2-bromo-5-fluoro toluene (1.9 mL, 15.0 mmol) dropwise at −78°C. over 15 min. The reaction mixture was allowed to warm to 0° C. over 1hour and was then cooled to −78° C. 1-Benzyl-4-piperidone (1.48 mL, 8.0mmol) was added to the white slurry and the reaction mixture was warmedto 0° C. over 2 hours. The reaction was quenched with 10 mL of saturatedNH₄Cl solution. The organic layer was extracted with diethyl ether (2×50mL) and the combined organic layers were washed with brine (100 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered, and thesolvent was removed in vacuo to obtain a yellow oil. It was purified bycolumn chromatography over silica gel with 3:2 hexane-EtOAc as theeluting system to obtain1-benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol as a yellow thickoil (1.1 g, 46% yield).

[0171] b.1-Benzyl-4-(4-Fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine

[0172] To a solution of1-benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol (1.1 g, 3.68 mmol)in 100 mL toluene was added p-toluenesulfonic acid monohydrate (1.39 g,7.35 mmol) and the resulting solution was heated to reflux for 8 hours.The suspension was cooled and the basified with 10% KOH solution andextracted with EtOAc (2×50 mL). The organic layer was washed with brine(30 mL). The organic layer was separated, dried over Na₂SO₄, filtered,and the solvent was removed in vacuo to obtain1-benzyl-4-(4-fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine as apale yellow oil (0.9 g, 87% yield). It was used in the next step withoutfurther purification.

[0173] c. 4-(4-Fluoro-2-methyl)-phenyl-piperidine

[0174] To a cooled suspension of 10% Pd-C (0.1 g) in 10 mL methanol wasadded a solution of1-benzyl-4-(4-fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine (0.9 g,3.2 mmol) in 20 mL of methanol and the resulting suspension washydrogenated at room temperature under 1 atm of hydrogen for 10 hours.The suspension was filtered through a pad of celite and the solvent wasremoved from the filtrate to obtain4-(4-fluoro-2-methyl)-phenyl-piperidine which was converted into itshydrochloride salt (0.62 g, 99% yield). It was used in the next stepwithout further purification.

[0175] d. (+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide(Compound 2)

[0176] 4-(4-Fluoro-2-methyl)-phenyl-piperidine was converted into3-amino-propyl-4-(4-fluoro-2-methyl)phenylpiperidine by the same manneras described in section I, part 3b. This was further converted into(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl3-amide bythe same manner as described in section I part 3c. White solid.M.P.=92°-96° C.; [α]D=+19.1 (c=0.12, MeOH); Analysis calculated forC₂₆H₃₁N₃O₃F₃Cl.0.5 CHCl₃: C, 54.35; H, 5.42; N, 7.17. Found: C, 54.20;H, 5.51; N, 6.81.

[0177] 5. Morpholinone example: the synthesis of(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro)phenyl -piperidin-1-yl]-propyl}-amide (Compound 3)

[0178] a. 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine

[0179] To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol,55.0 mL of 2.0 M solution) in 150.0 mL THF at 0° C. was added1-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resultingsolution was stirred under argon atmosphere for 1.5 hours and thenquenched with 100.0 mL of saturated NH₄Cl solution. The organic layerwas separated and the aqueous layer was extracted with 100.0 mL of Et₂O.The combined organic extracts were washed with brine, separated, anddried over Na₂SO₄. The solution was filtered and the solvent was removedin vacuo to obtain a yellow oil which was purified by passing through asilica gel column with 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc asthe eluting system. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-ol wasobtained as a pale yellow oil in 89% yield (13.9 g). It was dissolved in150.0 mL of toluene and p-toluenesulfonic acid monohydrate (50.0 mmol,9.5 g) was added. The resulting suspension was heated to reflux for 8hours. After the suspension was cooled, it was basified with 3 N NaOHsolution and was extracted with Et₂O (2×50 mL). The organic extractswere combined, washed with brine, and the organic layer was dried overNa₂SO₄. The solvent was removed in vacuo to obtain1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine as a yellowviscous oil (12.0 g, 92% yield) which was used in the next step withoutfurther purification.

[0180] b. 4-(4-fluoro)-phenyl-piperidine

[0181] To a solution of1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (45.0 mmol,12.0 g) in 100 mL MeOH was added 1.0 g of Pd(OH)₂ and the resultingsuspension was hydrogenated under 200 psi of H₂ in a stainless steelbomb for two days. The suspension was passed through a pad of celite andthe filtrate was concentrated in vacua to obtain4-(4-fluoro)-phenylpiperidine (7.5 g, 94%) as a viscous oil.

[0182] c. (+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide (Compound 3)

[0183] 4-(4-Fluoro)-phenyl-piperidine was converted into3-[4-(4-fluoro-phenyl)-piperidin-1-yl]-propylamine in the same manner asdescribed in section I part 3b. This was further converted into(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-(3-[4-(4-fluoro) phenyl-piperidin-1-yl]-propyl}-amide by the samemanner described section I part 3c. White solid. M.P.=86°-90° C.; [α]D=+22.7 (c=0.23, MeOH) ; Analysis calculated for C₂₅H₂₉N₃O₃F₃Cl.0.4CHCl₃: C, 54.51; H, 5.29; N, 7.51. Found: C, 54.74; H, 5.48; N, 7.26.

[0184] 6.Morpholinone example:3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carboxamido)-phenyl-piperiazin-1-yl]-propyl}-amide(Compound 4)

[0185] a. 1-(2-carboxamidophenyl)piperazine

[0186] Concentrated sulfuric acid (15 mL) was added to1-(2-cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a round bottomflask, and the resulting slurry was stirred at room temperature for 48hours. The reaction mixture was poured on crushed ice very slowly andthen basified (pH 9) with 50% solution of NaOH. The aqueous layer wasextracted several times with EtOAc, dried over K₂CO₃, filtered, and thesolvent was evaporated. 1-(2-carboxamidophenyl)piperazine was obtainedas an off-white solid (1.2 g, 73%).

[0187] b.3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid{3-[4-(2-carboxamido)-phenyl-piperiazin-1-yl]-propyl}-amide(Compound 4)

[0188] 1-(2-carboxamidophenyl)piperazine was converted into1-(3-amino-propyl)-4-(2-carboxamido)-phenyl-piperazine in the samemanner as described in section I part 3b. This was further convertedinto 3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carboxamido)-phenyl- piperiazin-1-yl]-propyl} -amide inthe same manner as described in section I part 3c. Pale yellow powder.M.P.=118°-122° C.; Analysis calculated for C₂₅H₃₀N₅O₄F₂Cl.1.1 hexane: C,59.98; H, 7.23; N, 11.07. Found: C, 60.20; H, 7.50; N, 11.32.

[0189] 7. Morpholinone example: synthesis of3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-nitro)-phenyl-piperazin-1-yl]-propyl}-amide (Compound 5)

[0190] a. 1-(2-nitrophenyl)-piperazine

[0191] A heterogenous reaction mixture containing 2-bromonitrobenzene(2.02 g, 10.0 mmol) and piperazine (4.3 g, 50.0 mmol) was heated at 100°C. for 10 hours. The orange-red solid was extracted with ethyl acetateand washed thoroughly with 3 N NaOH solution followed by brine. Theorganic layer was separated and dried over Na₂SO₄, filtered and thesolvent was removed in vacuo. The resulting red oil was purified bycolumn chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1EtOAc/MeOH) to yield 1-(2-nitrophenyl)-piperazine as an orange-red oil(1.90 g, 92%) . It was characterized as a hydrochloride salt. Analysiscalculated for C₁₀H₁₄N₃O₂Cl.0.10 CHCl₃: C, 47.46; H, 5.56; N, 16.44.Found: C, 47.63; H, 5.69; N, 16.42.

[0192] b. 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-nitro)-phenyl-piperazin-1-yl]-propyl}-amide (Compound 5)

[0193] 1-(2-nitrophenyl)-piperazine was converted into1-(3-amino-propyl)-4-(2-nitrophenyl)-phenyl-piperazine in the samemanner as described in section I part 3b. This was further convertedinto 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4 -carboxylicacid-{3-[4-(2-nitro)-phenyl-piperiazin-1-yl] -propyl}-amide in the samemanner as described in section I part 3c. Pale yellow sticky solid.M.P.=68°-72° C.; Mass spec. 504 (M+1, 100%); Analysis calculated forC₂₄H₂₈N₅O₅F₂Cl.1.2 hexane: C, 58.25; H, 7.02; N, 10.89. Found: C, 58.39;H, 7.02; N, 10.13.

[0194] 8. Morpholinone example:3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-methyl)-phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propyl}-amide(Compound 6)

[0195] a. 4-(4-Methyl)-phenyl-4-(2-methyl)phenyl piperidinehydrochloride

[0196] To a 100 mL round bottom flask equipped with a rubber septum anda stirring bar was added 4-hydroxy-4-(4-methyl)phenyl-piperidine (1.25g, 6.54 mmol) followed by 20 mL of anhydrous toluene. The resultingsolution was stirred at room temperature under argon atmosphere and thenAlCl₃ (1.4 g, 10.2 mmol) was added in one portion. An exotherm wasobserved. The reaction mixture was stirred for 10 hours and then pouredcarefully over 100 ml of ice-water. The white solid that precipitatedout was filtered and washed thoroughly with water followed by diethylether to obtain 4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidinehydrochloride (1.95 g, 99%) as a white solid. Mass spectrum: 266 (M+1,100%). Analysis calculated for C₁₉H₂₄NCl.0.15 CH₂Cl₂: C, 73.11; H, 7.79;N, 4.45. Found: C, 73.33; H, 7.82; N, 3.92.

[0197] b. 3-[4-(4-methyl-phenyl-4-(2-methyl)phenylpiperidin-1-yl]propylamine

[0198] To a solution of 4-(4-methyl)-phenyl-4-(2-methyl)phenylpiperidine hydrochloride (2.6 g, 9.8 mmol) in 100 mL dioxane was added3-bromo-N-tert-butoxycarbonyl-propylamine (2.57 g, 10.8 mmol) and K₂CO₃(4.06 g, 29.4 mmol) and the resulting suspension was heated to refluxfor 10 hours. The suspension was allowed to cool, filtered, and thesolvent was evaporated to obtain a yellow residue which was purified bycolumn chromatography (Rf=0.4, 3:1 EtOAc/MeOH) to obtain3-[4-(4-methyl-phenyl-4-(2-methyl)phenylpiperidin-1-yl]-N-tert-butoxycarbonyl-propylamine as a yellow oil (2.30g). It was dissolved in 60 mL of CH₂Cl₂ and 10.0 mL of trifluoroaceticacid was added with stirring at room temperature under argon atmospherefor 1 hour. The solvent was evaporated in vacuo and the residue wasbasified to pH 10 by adding minimum amount of 1 N KOH solution. Theproduct was extracted with CH₂Cl₂ (3×25 mL), dried over MgSO₄, filtered,and the solvent was removed in vacuo to obtain3-[4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidin-1-yl]propylamine asa yellow oil (1.39 g, 44% for two steps).

[0199] c. 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-methyl)-phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propyl}-amide(Compound 6)

[0200] 3-[4-(4-methyl-phenyl-4-(2-methyl)phenylpiperidin-1-yl]propylamine was converted into3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic acid-{3-[4-(2-methyl)-phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propyl}-amidein the same manner as described in section I part 3c. Yellow stickysolid.; Mass spec. 562 (M+1, 100%); Analysis calculated forC₃₃H₃₈N₃O₃F₂Cl.0.75 CH₂Cl₂: C, 61.25; H, 6.02; N, 6.35. Found: C, 61.07;H, 6.46; N, 5.95.

[0201] 9. Morpholinone example: the synthesis of3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethyl}]-amide (Compound 7)

[0202] A general procedure was utilized to form3-[4-cyano-4-(phenyl)cyclohex-1-yl] -ethylamine. A mixture of4-cyano-4-aryl-cyclohexanone (48.7 mmol) and ethylenediamine (8.78 g,146 mmol) and p-toluenesulfonic acid (92 mg) in benzene (200 mL) wasrefluxed for 4 hour with Dean—Stark trap to remove the water thatformed. Solvent was evaporated and the residue was redissolved inmethanol (60 mL) and cooled to 0° C. Sodium borohydride (6.45 g) wasadded in portions and the mixture was stirred at room temperature for 3hours. Solvent was evaporated, the residue was dissolved indichloromethane (300 mL), washed with brine (3×500 mL), dried (potassiumcarbonate), and the solvent evaporated to leave the product as a paleyellow viscous oil (90-95%). The product was found to contain thecis/trans isomers in a ratio of about 9:1. Careful chromatography ofthis mixture with chloroform/methanol/2 M ammonia in methanol (100/10/5to 100/20/10) yielded several earlier fractions enriched in trans isomerwith respect to the amino and cyano groups. Later fractions elutedcontained almost pure cis isomer relative to the amino and cyano groups.3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethylamine was converted to3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethyl}]-amide in the samemanner as described in section I part 3c. Yellow powder.; M.P.=85°-89°C.; Analysis calculated for C₂₆H₂₉N₄O₃F₂Cl.1.0 CH₂Cl₂: C, 53.70; H,5.17; N, 9.28. Found: C, 53.78; H, 5.30; N, 8.87.

[0203] 10. Morpholinone example: the synthesis of3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl}-amide(Compound 8)

[0204] a. 1-(2-carbomethoxyphenyl)-piperazine

[0205] To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in1,6-dioxane (100 ml) at room temperature was added piperazine (15.3 g,178 mmol) and K₂CO₃ (4.92 g, 35 mmol). The resulting mixture was heatedto reflux for 7 days after which the reaction mixture was cooled to roomtemperature. The solvent and the excess piperazine were removed in vacuoalong with heating with a hot water bath. The residue was dissolved in1N NaOH solution, extracted with CH₂Cl₂ (6×30 ml), and dried overNa₂SO₄. The solvent was removed in vacuo to obtain1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0 g, 26%).

[0206] b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl)-amide(Compound 8)

[0207] 1-(2-Carbomethoxyphenyl)-piperazine was converted into1-(3-amino-propyl)-4-(2-carbomethoxyphenyl)-piperazine in the samemanner as described in section I part 3b. This was further convertedinto 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-(3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl}-amide in thesame manner as described in section I, part 3c. Yellow hygroscopicsolid; Analysis calculated for C₂₆H₃₂N₄O₅F₂Cl₂0.3 CH₂Cl₂: C, 51.37; H,5.34; N, 9.11. Found: C, 51.16; H, 5.37; N. 8.27.

[0208] 11. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide (Compound9)

[0209] a. 3-[4-Carbomethoxy-4-phenyl-piperidin-1-yl]-ethylamide

[0210] To a solution of 4-carbomethoxy-4-phenyl-piperidine (0.4 g, 2.1mmol) in 30 mL dioxane was added3-bromo-N-tert-butoxycarbonyl-ethylamine (0.5 g, 2.5 mmol) and K₂CO₃(0.6 g, 6.0 mmol) and the resulting suspension was heated to reflux for10 hours. The suspension was allowed to cool, was filtered, and thesolvent was evaporated to obtain a yellow residue which was purified bycolumn chromatography (Rf=0.4, 3:1 EtOAc/MeOH) to obtain3-[4-carbomethoxy-4-phenyl-piperidin-1-yl]—N-tert-butoxycarbonyl-ethylamine as a yellow oil (0.35 g). It wasdissolved in 15 mL of CH₂Cl₂ and 3.0 mL of trifluoroacetic acid wasadded with stirring at room temperature under argon atmosphere for 1hours. The solvent was evaporated in vacuo and the residue was basifiedto pH 10 by adding minimum amount of 1 N KOH solution. The product wasextracted with CH₂Cl₂ (3×25 mL), dried over MgSO₄, filtered and thesolvent was removed in vacuo to obtain3-[4-carbomethoxy-4-phenyl-piperidin-1-yl]ethylamine as a yellow oil(0.25 g, 55% for two steps). Yellow solid; M.P.=113°-117° C.; Analysiscalculated for C₂₆H₃₀N₃O₅F₂Cl.0.3 Et₂O: C, 58.32; H. 6.14; N, 6.81.Found: C, 58.31; H, 5.94; N, 7.50.

[0211] b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide (Compound9)

[0212] 3-[4-Carbomethoxy-4-phenyl-piperidin-1-yl]-ethylamine wasconverted into 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide in thesame manner as described in section I, part 3c. Yellow solid;M.P.=113°-117° C.; Analysis calculated for C₂₆H₃₀N₃O₅F₂Cl.0.3 Et₂O: C,58.32; H, 6.14; N, 6.81. Found: C, 58.31; H, 5.94; N, 7.50.

[0213] 12. Morpholinone example: synthesis of3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-amide (Compound 10)

[0214] a. 3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine

[0215] 3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine was synthesizedfrom commercially available 4-hydroxy-4-phenyl piperidine using the sameprocedure as described in section I, part 3b.

[0216] b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-amide (Compound 10)

[0217] 3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine was convertedinto 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-amide in the samemanner as described in section I, part 3c. Yellow solid.; M.P.=85°-88°C.; Analysis calculated for C₂₅H₃₀N₃O₄F₂Cl.0.2 MeOH: C, 58.61; H, 6.01;N, 8.14. Found: C, 58.29; H, 6.42; N, 7.98.

[0218] 13. (−)-3-Phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5′-fluoro-2′-methoxy)phenyl-4-phenyl-piperidin-1-yl]-propyl}-amide(Compound 11)

[0219] 3-Phenyl-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenyl esterwas prepared from R-(−)-phenyl glycinol in the same manner as describedin section I, parts 1d-g. It was coupled with3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl)-propylamine(section I parts 3α-b) in the same manner as described in section I,part 3c. White powder. M.P.=105°-109° C.; [α]_(D)=−49.0 (c=0.12, MeOH)Analysis calculated for C₃₂H₃₇N₃O₄F₂Cl.1.0 CH₂Cl₂: C, 59.42; H, 5.89; N,6.30. Found: C, 59.51; H, 6.22; N, 6.05.

[0220] II. Synthesis of Substituted Morpholinone Examples

[0221] 1. Synthesis of3-(3,4-difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (Scheme 3)

[0222] a. 2-Hydroxy-1-pyrrolidin-1-yl-propan-1-one

[0223] The procedure has been reported (Vilarrasa et al., TetrahedronLett. 38, 1633, 1997). S-(+)-Methyl lactate (48.03 mmol, 5.0 g) andpyrrolidine (52.8 mmol, 4.4 mL) were mixed in a round bottom flask andthe reaction mixture was allowed to stir at room temperature for fourdays. Methanol was distilled off using a short path distillationapparatus to obtain 2-hydroxy-1-pyrrolidin-1-yl-propan-1-one as a yellowoil. It was used in the next reaction without further purification.

[0224] b.2-(tert-Butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one

[0225] To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1-one (47.0mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 g),N,N-dimethyl-4-aminopyridine (4.7 mmol, 0.57 g) at room temperature.tert-Butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g) was then addedwhile stirring. Some exotherm was observed. The initial pale yellowsolution turned brown-red in color and some precipitate was observedafter 30 min. The reaction mixture was stirred overnight and was thenfiltered through a sintered glass funnel. The solid was washed withEt₂O. The filtrate was diluted with water (150 mL) and it was extractedwith Et₂O (2×100 mL). The organic extracts were combined and washedsuccessively with water (100 mL), saturated NH4Cl solution, and theorganic layer was separated. It was dried over Na₂SO₄, filtered, and thesolvent was removed in vacuo to obtain2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one as agolden yellow oil (10.4 g, 86% yield). The product was judged to be >95%pure by NMR and was used in next step without any purification.

[0226] c.2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-one

[0227] To a round bottom flask containing 72.0 mL of THF at −78° C. wasadded a solution of n-butyllithium in hexane (72.0 mmol, 45.0 mL) underan argon atmosphere followed by 1-bromo-3,4-difluorobenzene (72.0 mmol,8.1 mL). A solution of2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one (60.0mmol, 15.4 g) in 10.0 mL THF was then added in a steady stream and theorange colored solution was stirred for 35 min at −78° C. It wasquenched with 20.0 mL of saturated NH₄Cl solution and was allowed toattain room temperature. The solution was extracted with Et₂O (2×50 mL),washed with brine, and the organic layer was dried over Na₂SO₄. Thesolution was filtered, and the solvent was removed in vacuo to obtainthe product as an orange oil. The crude product was subjected to silicagel flash column chromatography (9:1 hexane/EtOAc to 4:1 hexane/EtOAc asthe eluent system).2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-onewas obtained as a pale yellow oil (14.1 g, 78% yield, 96% based on therecovered starting material).

[0228] d.2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-one-oxime

[0229] To a solution of2-(tert-butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-one(13.7 mmol, 4.1 g) in 60.0 mL of methanol was added sodium acetate (3.76g) and hydroxylamine hydrochloride (1.24 g) and the resulting solutionwas stirred at room temperature overnight. Methanol was then removed invacuo and the resulting residue was extracted with EtOAc (2×50 mL) andbrine. The organic layer was separated, dried over Na₂SO₄I filtered, andthe solvent was removed in vacuo.2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-one-oximewas obtained as a colorless oil (4.04 g, 94% yield) and was used in thenext step without further purification.

[0230] e. 1-Amino-1-(3,4-difluorophenyl)-propan-2-ol

[0231] To a solution of2-(tert-butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-one-oxime(12.2 mmol, 3.84 g) in 20.0 mL of Et₂O was added a 1.0 M solution oflithium aluminum hydride (25.0 mmol, 25.0 mL) at 0° C. under an argonatmosphere. After 1 hour, the solution was heated to reflux for 2 hoursat which time some solid was observed. The reaction mixture was cooledto 0° C. and then quenched sequentially with water (1.0 mL), 1.0 N KOH(1.0 mL), and water (3.0 mL). The residue was filtered and the solid waswashed with warm Et₂O (20.0 mL). The filtrates were combined and driedover Na₂SO₄. The solution was filtered and the solvent was removed invacuo to obtain 1-amino-1-(3,4-difluorophenyl)-propan-2-ol as acolorless oil which solidified into a low melting solid (2.1 g, 92%yield). It was used in the next step without purification.

[0232] f. 3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester

[0233] 1-Amino-1-(3,4-difluorophenyl)-propan-2-ol was converted to3-(3,4-difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester in the same manner as described in section I,parts 1d-g or 2.

[0234] 2. Substituted morpholinone example:(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine -4-carboxylicacid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide (Compound 12)

[0235] 3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (section II part 1) was coupled to3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propylamine (section I part 5) inthe same manner as described in section I, part 3c. Yellow hygroscopicsolid. M.P.=69°-73° C.; Mass spec. 490 (M+1, 100%); [α] D=+20.2 (c=0.08,MeOH). Analysis calculated for C₂₆H31N₃O₃F₂Cl.2.0 H₂O: C, 57.51; H,6.50; N, 7.74. Found: C, 57.61; H, 6.15; N, 7.27.

[0236] 3. Substituted morpholinone example:(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine -4-carboxylicacid-{3-[4-(4-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]-propyl}-amide(Compound 13)3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (section II part 1) was coupled to3-[4-(4-fluoro-2-methoxy)phenyl -4-phenyl-piperidin-1-yl]-propylamine(section I, part 3α-b) in the same manner as described in section I,part 3c. Yellow powder. M.P.=95°-99° C.; Mass spec. 596 (M+1, 100%);[α]D=+56.9 (c=0.13, MeOH) Analysis calculated for C₃₃H₃₆N₃O₄F₂C_(0.1.5)CH₂Cl₂: C, 54.56; H, 5.31; N, 5.53. Found: C, 54.51; H, 5.63; N, 5.20.

[0237] 4. Substituted morpholinone example:(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-{3-[4-(cyano-4-phenyl-piperidin-1-yl]-propyl}-amide (Compound 14)

[0238] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthalimide

[0239] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassiumcarbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L)was stirred and heated at 100°-110° C. for 8 hours. About 80% of thesolvent was evaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96°-98° C.

[0240] b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine

[0241] To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide (112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30mL) was added and the mixture was stirred and refluxed for 20 hours. Itwas cooled, the white solid formed was filtered and washed with moremethanol (200 mL). Solvent was evaporated from the filtrate and residuewas dried under vacuum for 4 hours. Chloroform (500 mL) was added tothis, stirred for 1 hour and filtered. The white solid was washed withmore chloroform (200 mL), the solvent was evaporated from the combinedfiltrates to leave the product as an oil (70 g, 96%).

[0242] c.(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-{3-[4-(cyano-4-phenyl-piperidin-1-yl]-propyl}-amide3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (section II, part 1) was coupled to3-[4-(cyano-4-phenyl-piperidin-1-yl]-propylamine in the same manner asdescribed in section I, part 3c. White powder. M.P.=191°-194° C.; Massspec. 497 (M+1, 10096); [α]_(D)+23.1 (c=0.09, MeOH) Analysis calculatedfor C₃₃H₃₆N₃O₄F₂Cl.0.35 CH₂Cl₂: C, 58.38; H, 5.68; N, 9.96. Found: C,58.57; H, 6.03; N, 9.72.

[0243] III. Synthesis of Substituted Morpholinone Examples (Schemes 4aand 4b)

[0244] 1. Synthesis of (+)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (Scheme4a)

[0245] a. Amino-(3,4,-difluorophenyl)-acetonitrile

[0246] Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.18 mol)in MeOH (500 mL) in a round bottom flask was bubbled ammonia gas for twohours at room temperature. The flask was then cooled to 0° C. andtrimethylsilyl cyanide (1.3 eq., 0.23 mmol) was then added slowly. Thereaction mixture was stirred for 2 hours when TLC analysis indicted thatthe reaction was complete (R_(f)=0.35, 3:2 hexane/EtOAc). Solvent wasremoved in vacuo and the residue was subjected to flash columnchromatography on silica gel to obtain 25.0 g (81%) ofamino-(3,4-difluorophenyl)-acetonitrile as a yellow syrup.

[0247] b. Methyl 2-amino-2-(3,4-difluorophenyl)acetate

[0248] To a well stirred solution ofamino-(3,4-difluorophenyl)-acetonitrile (22.0 g., 0.130 mol), a solutionof HCl in MeOH (200 mL) was added at room temperature. The resultingyellow solution was stirred at room temperature for 10 hours and thenheated to reflux for 1.5 hours. After cooling, the solvent was removedin vacuo and the resulting yellow solid was dissolved in water (200 mL).The aqueous solution was then carefully basified with 20% NaOH solutionto pH 9. The aqueous layer was extracted with CH₂Cl₂ (3×100 mL). Theorganic layer was separated and dried over Na₂SO₄, filtered and thesolvent was removed in vacuo to obtain 22.2 g (84%) of methyl2-amino-2-(3,4-difluorophenyl)acetate as a brownish yellow liquid. Itwas used in the next step without purification.

[0249] c. (+)-1-(3,4-Difluorophenyl)-2,2-dimethyl-2-hydroxypropylamine

[0250] To a well-stirred solution of methyl2-amino-2-(3,4-difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrousether (200 mL) at 0° C. was added a solution of methylmagnesium bromidein ether (3 M, 87 mL, 261 mmol) over 10 minutes. The mixture was stirredat 0° C. for 2.5 hours and allowed to warm to room temperature. After 12hours, the mixture was carefully poured onto a mixture of ice (300 g)and saturated ammonium chloride (50 g). The ether layer was separatedand the aqueous layer was extracted with more ether (4×200 mL). Thecombined extracts were dried over magnesium sulfate and the solventevaporated. The crude product was purified by column chromatography onsilica gel using chloroform/methanol/2M ammonia in methanol (1000:20:10,1000:40:20, 1000:80:40) as eluents to give the product as an oil (6.5 g,62%). The ¹H—NMR and MS confirmed this to be the desired product.

[0251] d. (+)-1-(3,4-Difluorophenyl)-2,2-dimethyl-2-hydroxypropylaminechloroacetamide

[0252] To a solution of1-(3,4-difluorophenyl)-2,2-dimethyl-2-hydroxypropylamine (10.20 g, 50.70mmol) and triethylamine (5.0 mL) in dichloromethane (100 mL) at −78 ° C.was added chloroacetyl chloride (4.64 mL, 60.83 mmol) dropwise over 10min. The resulting mixture was stirred at −78° C. for 2 hours and wasthen slowly warmed to −40° C. over one hour. The reaction was quenchedby adding H₂O (20 mL) and the mixture was extracted with EtOAc (2×100mL). The ethyl acetate extracts were dried over MgSO₄ and concentratedto a residue which was purified by column chromatography (SiO₂, 30% to50% EtOAc/Hex) to afford the product as a colorless oil (6.50 g, 46 %yield).

[0253] e. (+)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholineLithium bis(trimethylsilyl)amide (5.68 mL, 1.0 M in THF) was added to astirred solution of 1-(3,4-difluorophenyl)-2-methyl-2-hydroxypropylamine2-chloroacetamide (1.21 g, 4.37 mmol) in THF at 0° C. The resultingmixture was stirred while warmed to room temperature over 30 min. It wasthen heated to 50° C. and stirred for 60 min. The mixture was quenchedwith water (2 mL) and extracted with EtOAc (2×100 mL). The extracts weredried (Na₂SO₄) and the solvent was evaporated. The crude product waspurified by column chromatography (SiO₂, 50:50 to 90:10 EtOAc/Hexanes)to give 0.36 g (34%) of morpholinone as a pale yellow oil.

[0254] f. (+)-4—Nitrophenyl 2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate

[0255] To a solution of(+)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine (240 mg, 0.996mmol) in THF (10 mL) at −78° C. was added lithiumbis(trimethylsilyl)amide (1.10 mL, 1.0 M in THF). The mixture wasstirred for 30 min at 0° C. and then cooled back to −78 ° C. The mixturewas transferred via a cannula to a precooled solution of 4-nitrophenylchloroformate (605 mg, 3.0 mmol) in THF (10 mL) at −78° C. The resultingmixture was stirred while warmed to room temperature over 3 hours. Thereaction was quenched with water (2 mL) and extracted with EtOAc (2×100mL). The organic layer was dried with Na₂SO₄ and the solvent wasevaporated. The residue was purified by column chromatography (SiO₂,40:60 EtOAc/Hexanes) to afford 0.328 g (81%) of the product as a paleoil. 2. Synthesis of enantiomerically pure 4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (Scheme4b)

[0256] a. (S)-(+)-O-Acetylmandelyl(+/−)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine-3-amide

[0257] To a solution of (S)-(+)-o-acetylmandelic acid (408 mg, 2.10mmol) in Et₂O (50 mL) and triethylamine (212 mg) under argon at −78° C.,was added 2,2,2-trimethylacetyl chloride (272 mg, 2.10 mmol). Theresulting mixture was warmed to 0° C. in ice-bath for 10 min to yieldthe acid chloride and it was then cooled back to −78° C. At the sametime,(+/−)-2,2-dimethyl-3-(3,4-difluorophenyl)-6-oxo-morpholine (406 mg,1.68 mmol) was dissolved in THF (15 mL) in another dried flask andcooled to −78° C., and n-BuLi (0.75 mL, 2.5 M) was added dropwise. Theresulting solution was stirred for 10 min and was then transferred tothe acid chloride via a cannula. The reaction mixture was stirred for 10min at −78° C. and was then warmed to 0° C. and stirred for 1 hourbefore quenching with water (2 mL). The mixture was extracted with EtOAc(2×50 mL), dried (Na₂SO₄), and the solvent was evaporated. The crudeproduct was purified by column chromatography (SiO₂, 15:85 to 30:70EtOAc/Hexanes) to obtain 0.476 g of the two diastereomers as purecompounds. (combined yield: 68%) (Higher Rf product: 318 mg; Lower R.product: 158 mg)

[0258] b. (−)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine

[0259] LiOH.H₂O (281 mg, 6.71 mmol) was added to a solution of the amidefrom the previous step (Higher R, compound, 280 mg, 0.671 mmol) in THF(20 mL), H₂O (2 mL) and H₂O₂ (5 mL). The resulting mixture was stirredvigorously for one hour. The mixture was filtered and the filtrate wasextracted with EtOAc (2×50 mL), dried (Na₂SO₄), and the solvent wasevaporated. The crude product was purified by column chromatography(SiO_(2, 50:50) to 90:10 EtOAc/Hexanes) (0.120 g, 74%). optical rotation[α]D=-10-0 (c=4.5, MeOH).

[0260] c. (+)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine

[0261] Prepared in the same manner as described in section III, part 2bfrom 150 mg of amide (lower R_(f) compound). Yield: 65 mg (75%);[α]D=+9.6 (c=2.5, MeOH)

[0262] d. Enantiomerically pure 4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5- oxo -morpholinecarboxylate

[0263] The enantiomerically pure4-nitrophenyl-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylateswere prepared from(−)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine and(+)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine in a similarmanner as described in section III, part 1d.

[0264] 3. Typical reaction sequence for the coupling of side chains(RNH₂) with activated morpholinones (Scheme 4) Synthesis ofN-4-[3-(4-methoxycarbonyl-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride (Compound 15)

[0265] a. 4 -Methoxycarbonyl-4-phenylpiperidine

[0266] To a stirred solution of H₂SO₄ (16 mL) in MeOH (400 mL),4-phenyl-4-piperidinecarboxylic acid 4-methyl benzenesulfonate (37.7 g,0.1 mole) was added and the mixture was stirred and refluxed for 8hours. Excess methanol was evaporated at reduced pressure and theresidue was poured into a mixture of ice and 6 N NaOH. The pH wasadjusted to 10-11 by adding more 6 N NaOH and extracted with CH₂Cl₂(3×150 mL). The combined CH₂Cl₂ extracts were dried (MgSO₄) and thesolvent evaporated to leave the desired product as a viscous oil. Theproduct (20.2 g, 92%) was used without further purification.

[0267] b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine

[0268] A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g, 0.039mol), 3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassiumcarbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in1,4-dioxane (200 mL) was stirred and refluxed for 24 hours. Dioxane wasevaporated at reduced pressure, the residue was treated with ice-cold 6N NaOH (400 mL) and extracted with CH₂Cl₂ (4×120 mL). Solvent wasevaporated from the combined dried (K₂CO₃) extracts and the residue waspurified by column chromatography on silica gel using CHCl₃/MeOH/2 M NH₃in MeOH (20:2:1) as the eluent to afford the product as a viscous oil(7.8 g, 72%).

[0269] c. N-4-[3-(4-methoxycarbonyl-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

[0270] 4-Methylcarboxyl-4-phenyl-piperidinyl-N-propylamine (100 mg,0.384 mmol) was added to a stirred solution of(±)-4-nitrophenyl-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate(15 mg, 0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirredat room temperature overnight and purified by prep. TLC on silica gelusing EtOAc as the eluent to give 10 mg product (50%). The HCl salt wasprepared by treatment with 1 N HCl in ether.

[0271] 4. Substituted morpholinone example:

[0272] Methyl4-[2-([3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxomorpholino]carbonylamino)ethyl]amino-1-phenyl-1-cyclohexanecarboxylatehydrochloride (cis isomer) (Compound 16)

[0273] a. 2-[4-Methoxycarbonyl-4-phenyl-cyclohexylamino3 ethylamine

[0274] A mixture of 2-[4-cyano-4-phenylcyclohexylamino] ethylamine (2.34g, 10 mmol) and concentrated sulfuric acid (20 mL) was heated at 80°-85°C. for 10 hours. It was cooled to room temperature, mixed with anhydrousmethanol (200 mL), and refluxed for 20 hours. Solvent was evaporated andthe residue was poured onto ice (200 g) and basified to pH 11 byaddition of 6 N NaOH. It was extracted with dichloromethane (4×125 mL),dried (potassium carbonate) and solvent evaporated to leave the productas an oil (2.1 g, 76%). This product was a pure mixture of cis and transisomers. It was used in the next step without any further purification.

[0275] b. Methyl4-[2-([3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxomorpholino]carbonylamino)ethyl]amino-1-phenyl-1-cyclohexanecarboxylatehydrochloride (cis isomer)

[0276] 4-Methylcarboxyl-4-phenyl-cyclohexyl-amino-ethylamine (25 mg,0.091 mmol) was added to a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂C₁ ₂ (5 mL). The resulting mixture was stirred at RTovernight and purified by prep. TLC on silica gel using EtOAc as eluentto give 10 mg product (51%). MH⁺=544. The HCl salt was prepared bytreatment with 1 N HCl in ether.

[0277] 5. Substituted morpholinone example:N-4-[3-{4-(2-pyridyl}piperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride (Compound 17)

[0278] a. 1-Benzyl-4-cyano-4-(2-pyridyl)piperidine

[0279] To a mixture of N,N-bis-(2-chloroethyl)benzylamine (Szarvasi, E.,Eur. J. Med. Chem. Chim. Ther. 11(2), 115-124, 1976) (60 g, 22 mmol),2-pyridylacetonitrile (2.51 mL, 22 mmol) and tetrabutylammonium hydrogensulfate (0.26 g, 0.7 mmol) in toluene (10 mL), sodium hydroxide solution(2.43 g in 4.86 mL H₂O) was added over a 20 minute period. The reactionmixture was heated at 65° C. for 4 hours. The reaction mixture wascooled to room temperature, 10 mL of water was added and the solutionpartitioned between ethyl acetate (45 mL) and water. The organic layerwas dried over sodium sulfate, filtered and concentrated. Purificationof the crude product by column chromatography (hexane: EtOAc, 2:3) gave6.2 g (87%) of the title compound as a red solid; ¹H-NMR (CDCl₃): δ 2.05(d, J 13.1 Hz, 2H), 2.30 (t, J=13.2 Hz, 2H), 2.48 (t, J=13.2 Hz, 2 H),2.97 (d, J=12.1 Hz, 2 H), 3.57 (s, 2 H), 7.19-7.27 (m, 6 H), 7.30 (d,J=7.6 Hz, 1 H), 7.60 (t, J 7.6 Hz, 1 H ), 8.58 (d, J=4.6 Hz, 1 H).

[0280] b. 1-Benzyl-4-carboxamido-4-(2-pyridyl)piperidine

[0281] To 1-benzyl-4-cyano-4-(2-pyridyl) piperidine (4.5 g, 14.3 mmol),10 mL of conc. H₂SO₄ was added and the solution was stirred at roomtemperature for 24 hours. It was cooled to 0° C., diluted with icepieces and poured into crushed ice. The mixture was then carefullyneutralized with 50% NaOH solution. The reaction mixture was repeatedlyextracted with chloroform (3×25 mL), dried over sodium sulfate, filteredand concentrated to give 4.5 g (95 %) of the crude product which wasused as such for the subsequent step; ¹H—NMR (CDCl₃): δ 2.21-2.28 (m, 2H), 2.47 (s, 6 H), 3.41 (s, 2 H), 5.23 (s, 1 H), 6.40 (s, 1 H),7.12-7.29 (m, 6 H), 7.33 (d, J=7.6 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H),8.55 (d, J=4.6 Hz, 1 H).

[0282] c. 1-Benzyl-4-(2-pyridyl)-piperidine

[0283] To 1-benzyl-4-carboxamido-4-(2-pyridyl)piperidine (4.5 g, 13.5mmol) in anhydrous methanol (100 mL), HCl gas was bubbled through thesolution at 0° C. for 15 minutes. The reaction mixture was then refluxedfor 24 hours. It was cooled to room temperature, concentrated,neutralized with 50% NaOH and repeatedly extracted with chloroform (3×25mL). The combined organic layer was then dried over sodium sulfate,filtered and concentrated. Flash chromatography (hexane: ethylacetate,1:4) of the crude product yielded 1.72 g (50%) of the product as asyrup; ¹H—NMR (CDCl₃): δ 1.8-1.94 (m, 4 H), 2.11 (t, J=11.4 Hz, 2 H),2.70-2.72 (m, 1 H), 3.02 (d, J=11.4 Hz, 2 H), 3.54 (s, 2 H), 7.07-7.36(m, 7 H), 7.58 (t, J=7.6 Hz, 1 H) , 8.52 (d, J=4.6 Hz, 1 H).

[0284] d. 3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine

[0285] To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in drymethanol (25 mL), 10% palladium hydroxide (1.9 g) was added and thesolution was hydrogenated at 200 psi for 24 hours. The solution wasfiltered over celite, concentrated to give 2.1 g (99%) of4-(2-pyridyl)-piperidine which was used as such for the subsequent step.A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol),potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate(21.90 g, 100 mmol) in methanol was stirred at room temperature for 24hours. The reaction mixture was concentrated and partitioned between 250mL EtOAc and 50 mL water, dried over sodium sulfate, filtered andconcentrated. Purification of the crude product by column chromatography(hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a paleyellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86g, 11.4 mmol) in dioxane (20 mL),N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) andpotassium carbonate (3.16 g, 22.9 mmol) were added and the solution wasrefluxed for 24 hours. The reaction mixture was cooled to roomtemperature, concentrated and partitioned between 40 mL chloroform and 5mL water. The organic layer was dried over sodium sulfate, filtered andconcentrated. The crude product was purified by column chromatography(ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the requiredproduct as a colorless oil; ¹H—NMR (CDCl₃): δ 1.45 (s, 9 H), 1.54-1.69(m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H),5.41 ( s, 1 H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t,J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). ToN-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine(0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroaceticacid was added and the solution was stirred at room temperature for 1hour. The solution was concentrated, neutralized with 10% KOH solutionand extracted into 25 mL of dichloromethane. The organic layer was driedover sodium sulfate, filtered, and concentrated to give 0.098 g (100%)of 3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such forthe subsequent step.

[0286] e.N-4-[3-{4-(2-pyridyl}piperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

[0287] 4-(2-Pyridinyl)piperidinyl—N-propylamine (25 mg, 0.114 mmol) wasadded to a stirred solution of (+)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirred at RTovernight and purified by prep. TLC on silica gel using EtOAc as eluentto give 10 mg product (52%). MH⁺=487. The HCl salt was prepared bytreatment with 1 N HCl in ether.

[0288] 6. Substituted morpholinone example:N-4-[3-(4-Cyan-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride (Compound 18)

[0289] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide

[0290] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassiumcarbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L)was stirred and heated at 100°-110° C. for 8 hours. About 80% of thesolvent was evaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96°-98° C.

[0291] b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine

[0292] To a solution of3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide (112 g, 0.3 mol) inmethanol (1.5 L), hydrazine (30 mL) was added and the mixture wasstirred and refluxed for 20 hours. It was cooled, the white solid formedwas filtered and washed with more methanol (200 mL). Solvent wasevaporated from the filtrate and residue was dried under vacuum for 4hours. Chloroform (500 mL) was added to this, stirred for 1 hour andfiltered. The white solid was washed with more chloroform (200 mL), thesolvent was evaporated from the combined filtrates to leave the productas an oil (70 g, 96%).

[0293] c.N-4-[3-(4-Cyan-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

[0294] 4-Cyan-4-phenyl-piperidinyl—N-propylamine (25 mg, 0.103 mmol) wasadded to a stirred solution of (+)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂(5 ML). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as eluent to give 10 mg product (51%). MH⁺=511. The HCl salt wasprepared by treatment with 1 N HCl in ether.

[0295] 7. Substituted morpholinone example: (+)-N-4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride (Compound 18)

[0296] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide

[0297] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassiumcarbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L)was stirred and heated at 100°-110° C. for 8 hours. About 80% of thesolvent was evaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96°-98° C.

[0298] b. 3-(4-Cyano-4-phenylpiperidin-1-yl) propylamine

[0299] To a solution of3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide (112 g, 0.3 mol) inmethanol (1.5 L), hydrazine (30 mL) was added and the mixture wasstirred and refluxed for 20 hours. It was cooled, the white solid formedwas filtered and washed with more methanol (200 mL). Solvent wasevaporated from the filtrate and residue was dried under vacuum for 4hours. Chloroform (500 mL) was added to this, stirred for 1 hour andfiltered. The white solid was washed with more chloroform (200 mL), thesolvent was evaporated from the combined filtrates to leave the productas an oil (70 g, 96%).

[0300] c. (+)-N-4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

[0301] 4-Cyano-4-phenyl-piperidinyl—N-propylamine (40 mg, 0.165 mmol)was added to a stirred solution of (−)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂(5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as the eluent to give 16 mg product (85%). [α]D=+26.3 (c=0.8,CH₂Cl₂). MH⁺=511. The HCl salt was prepared by treatment with 1 N HCl inether.

[0302] 8. Substituted morpholinone example: (−)-N4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride (Compound 18)

[0303] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide

[0304] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassiumcarbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L)was stirred and heated at 100°-110° C. for 8 hours. About 80% of thesolvent was evaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96°-98° C.

[0305] b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine

[0306] To a solution of3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide (112 g, 0.3 mol) inmethanol (1.5 L), hydrazine (30 mL) was added and the mixture wasstirred and refluxed for 20 hours. It was cooled, the white solid formedwas filtered and washed with more methanol (200 mL). Solvent wasevaporated from the filtrate and residue was dried under vacuum for 4hours. Chloroform (500 mL) was added to this, stirred for 1 hour andfiltered. The white solid was washed with more chloroform (200 mL), thesolvent was evaporated from the combined filtrates to leave the productas an oil (70 g, 96%).

[0307] c. (−)-N4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

[0308] 4-Cyano-4-phenyl-piperidinyl—N-propylamine (40 mg, 0.165 mmol)was added to a stirred solution of (+)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂(5 ML). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC with EtOAc as eluent togive 14 mg product (74%). [α]_(D)=25.7 (c=0.7, CH₂Cl₂). MH⁺=511. The HClsalt was prepared by treatment with 1 N HCl in ether.

[0309] 9. Substituted morpholinone example:3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxylicacid-{2-[4-(2-pyridyl) piperidin-1-yl-1-methyl-ethyl}-amidehydrochloride (Compound 19)

[0310] a. N-(tert-Butoxycarbonyl)-L-alanine 4-(2-pyridyl)piperidin-1-ylamide

[0311] To a solution of N-(tert-butoxycarbonyl)-L-alanine (1.485 g,7.847 mmol) and 4-(2-pyridyl)piperidine (0.910 g, 5.60 mmol) indichloromethane ( 20 mL) at 0° C., was added N,N-dimethylaminopyridine(DMAP, 2.05 g, 16.8 mmol) and1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (DMAPECD,2.147 g, 11.2 mmol). The resulting mixture was stirred overnight whilewarmed up to room temperature. The reaction mixture was quenched withaqueous NH₄Cl (30 mL) and extracted with CH₂Cl₂ (30 mL×2). The combinedextracts were dried (K₂CO₃), concentrated, and purified by flashchromatography on silica gel (100% EtOAc) to obtain 2.09 g (80%) ofN-(tert-Butoxycarbonyl)-L-alanine 4-(2-pyridyl) piperidin-1-yl amide.

[0312] b.(S)—N-(tert-Butoxycarbonyl)amino-3-(4-(2-pyridyl)piperidin-1-yl)propane

[0313] To a solution of N-(tert-butoxycarbonyl)-L-alanine4-(2-pyridyl)piperidin-1-yl amide (0.650 g, 1.95 mmol) in THF (20 mL) at0° C. was added LAH (4.0 mL, 1.0 M in THF) dropwise. The resultingmixture was stirred for 3 hours before quenching with 1 mL of H₂O and 5mL of 1 N NaOH. The mixture was extracted with CH₂Cl₂ (30 mL×2). Thecombined extracts were dried (K₂CO₃), concentrated, and purified byflash chromatography on silica gel (chloroform: MeOH:2.0 M NH₃ inMeOH=100:5:1) to afford the product (0.479 g, 77%) as an colorless oil.

[0314] c. (S)-Amino-3-[4-(2-pyridyl)piperidin-1yl]propane

[0315] A solution of(S)—N-(tert-butoxycarbonyl)amino-3-[4-(2-pyridyl)piperidin-1-yl]propane(0.460 g, 1.44 mmol) in CH₂Cl₂ (10 mL) and TFA (5 mL) was stirred for 12hours at room temperature. The mixture was concentrated at reducedpressure and the residue was washed with 20% NaOH, and extracted withextracted with CH₂Cl₂ (50 mL×2). The combined extracts were dried(K₂CO₃), concentrated to yield the product (0.209 g, 66%) withoutfurther purification.

[0316] d.3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxylicacid-{2-[4-(2-pyridyl) piperidin-1-yl]-1- methyl-ethyl}-amidehydrochloride (Compound 19)

[0317] 4-(2-Pyridinyl)piperidinyl—N-(1-methyl)ethylamine (25 mg, 0.114mmol) was added to a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂(5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as eluent to give 10 mg product (55%). MH⁺=487. The HCl salt wasprepared by treatment with 1 N HCl in ether.

[0318] 10. Substituted morpholinone example:N-4-(2-[1-(2,4-Difluorobenzoyl)-4-piperidyllaminoethyl)-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride (Compound 20) (Scheme 5)

[0319] a. 4-(2,4-Difluorobenzoyl)piperidinone

[0320] To a suspension of 4-piperidinone monohydrate hydrochloride (2.00g, 13.28 mmol) in CH₂Cl₂ (40 mL) and triethylamine (5.0 mL) was added2,4-difluorobenzoyl chloride (2.84 g, 15.93 mmol). The resulting mixturewas stirred at room temperature for 5 hours before quenching withaqueous NaHCO₃ (30 mL). Extracted with EtOAc (3×50 mL), dried (MgSO₄),and concentrated to a residue which was purified by flash chromatography(EtOAc: Hexanes 9:1 to 1:1 ) afford product as an oil (2.25 g, 71%).

[0321] b. 2-{[4-(2,4-Difluorobenzoyl)piperidinyl]amino}-ethylamine

[0322] A solution of 4-(2,4-difluorobenzoyl)piperidinone (1.50 g, 6.27mmol) in benzene (40 mL) and ethylenediamine (4.0 mL) was refluxed for 6hours. The resulting mixture was concentrated to a residue which wasdissolved in MeOH (30 mL). The mixture was cooled (0° C.) and NaBH₄ (1.0g, 26.4 mmol) was slowly added. After stirred for an hour, the mixturewas concentrated and quenched with 1 N NaOH (50 mL). The mixture wasextracted with CH₂Cl₂ (5×20 mL), dried (K₂CO₃), and was concentrated.The residue was purified by flash chromatography (CHCl₃-MeOH-2 M NH₃ inMeOH 100:10:2 to 100:20:5) to afford the product as an pale yellow solid(670 mg, 38%).

[0323] c.3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxylicacid-{2-[1-(2,4-difluoro benzoylpiperidin-4-yl]-aminoethylamidehydrochloride

[0324] 4—N-(2,4-Difluorobenzoyl)-piperidinyl-amino-ethylamine (25 mg,0.088 mmol) was added to a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂(5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as eluent to give 10 mg product (49%). MH⁺=551. The HCl salt wasprepared by treatment with 1 N HCl in ether.

[0325] IV. Synthesis of Morpholine Example (Scheme 6)

[0326] 1. Synthesis of 3-(3,4-difluoro-phenyl)-morpholine-4-carboxylicacid[3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide (Compound 21)

[0327] a. 3-(3,4-Difluoro-phenyl)-morpholine

[0328] To a suspension of LiAlH₄ (6.0 mmol, 0.23 g) in 25.0 mL of Et₂Owas added a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (2.0mmol, 0.42 g) in 20.0 mL Et₂O and 5.0 mL THF at room temperature. Theresulting suspension was heated to reflux for 2 hours and was thenquenched with water and aq. NaOH solution. The solid was filtered offand the filtrate was dried over Na₂SO₄. The filtrate was then decantedand the solvent was removed in vacuo to obtain5-(3,4-difluoro-phenyl)-morpholine as a viscous oil. It was converted toits hydrochloride salt for its analysis. Yellow powder. M.P.=171°-173°C.; Mass spec. 200 (M+1, 100%). Analysis calculated for C₁₀H₁₂NOF₂Cl0.5acetone: C, 51.96; H, 5.61; N, 5.41. Found: C, 51.98; H, 5.70; N, 5.34.

[0329] b. 3-(4,4-Diphenyl-piperidin-1-yl)-propyl]-carbamicacid-4-nitro-phenyl ester

[0330] To a solution containing3-(4,4-diphenyl-piperidin-1-yl)-propylamine (0.8 mmol, 0.24 g) andtriethylamine (0.96 mmol, 0.13 mL) in 10 mL of THF was added4-nitrophenylchloroformate (0.94 mmol, 0.19 g) at 0° C. The solution wasallowed to reach room temperature over 1 hour. The solvent was removedand the product was passed through a short silica gel column with EtOAcas an eluent (Rf=0.25). 3-(4,4-Diphenyl-piperidin-1-yl)-propyl]-carbamicacid-4-nitro-phenyl ester was obtained as a yellow oil which wasimmediately used in the next step.

[0331] c. 3-(3,4-Difluoro-phenyl)-morpholine-4-carboxylicacid[3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide

[0332] To a solution of 3-(4,4-diphenyl-piperidin-1-yl)-propyl]-carbamicacid-4-nitro-phenyl ester (0.35 mmol, 150 mg) in 10.0 mL THF was added3-(3,4-difluoro-phenyl)-morpholine (0.4 mmol, 50 mg) at roomtemperature. The solvent was removed in vacuo and the residue wassubjected to silica gel column chromatography (8:1 EtOAc/MeOH as theeluting system). 3-(3,4-Difluoro-phenyl)-morpholine-4-carboxylic acid[3-(4,4-diphenyl-piperidin-1-yl)-propyl] -amide was obtained as a paleyellow oil which was converted into its hydrochloride salt by treatmentwith 1 N HCl in ether (34 mg, 61%). Yellow sticky solid. M.P.=71°-74°C.; Mass spec. 520 (M+1, 100%); Analysis calculated forC₃₁H₃₆N₃O₂F₂Cl.0.8 CH₂Cl₂: C, 61.21; H, 6.07; N, 6.73. Found: C, 61.45;H, 6.35; N, 6.27.

[0333] V. General Syntheses of Morpholinones and Morpholines

[0334] The examples described in Sections I-IV are merely illustrativeof the methods used to synthesize morpholine and morpholinonederivatives. Further derivatives may be obtained utilizing the methodsshown in Schemes 7-22. The substituents in Schemes 7-22 are described inthe Detailed Description. It may be necessary to incorporate protectionand deprotection strategies for substituents such as amino, amido,carboxylic acid, and hydroxyl groups in the synthetic methods describedabove to form morpholine and morpholinone derivatives. Methods forprotection/deprotection of such groups are well-known in the art, andmay be found, for example in Greene, T. W. and Wuts, P. G. M. (1991)Protective Groups in Organic Synthesis, 2nd Edition John Wiley & Sons,New York.

[0335] VI. Oral Composition

[0336] As a specific embodiment of an oral composition of a compound ofthis invention, 100 mg of one of the compounds described herein isformulated with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size 0 hard gel capsule.

[0337] VII. Pharmacological Profiles of the Compounds in Cloned HumanAdrenergic Receptors.

[0338] Binding affinities were measured for selected compounds of theinvention at six cloned human a, and U2 receptor subtypes, as well as atthe L-type calcium channel. The protocols for these experiments aregiven below.

[0339] 1. Protocol for the Determination of the Potency of a,Antagonists

[0340] The activity of compounds at the different human receptors wasdetermined in vitro using cultured cell lines that selectively expressthe receptor of interest. These cell lines were prepared by transfectingthe cloned cDNA or cloned genomic DNA or constructs containing bothgenomic DNA and cDNA encoding the human α-adrenergic receptors asfollows:

[0341] α_(1d) Human Adrenergic Receptor: The entire coding region ofα_(1d) (1719 bp), including 150 base pairs of 5′ untranslated sequence(5′ UT) and 300 bp of 3′ untranslated sequence (3′ UT), was cloned intothe BamHI and ClaI sites of the polylinker-modified eukaryoticexpression vector pCEXV-3, called EXJ.HR. The construct involved theligation of partial overlapping human lymphocyte genomic and hippocampalcDNA clones: 5′ sequence were contained on a 1.2 kb SmaI-XhoI genomicfragment (the vector-derived BamHI site was used for subcloning insteadof the internal insert-derived SmaI site) and 3′ sequences werecontained on an 1.3 kb XhoI-ClaI cDNA fragment (the ClaI site was fromthe vector polylinker). Stable cell lines were obtained bycotransfection with the plasmid α1A/EXJ (expression vector containingthe α_(1a) receptor gene (old nomenclature)) and the plasmid pGCcos3neo(plasmid containing the aminoglycoside transferase gene) into LM(tk−)cells using calcium phosphate technique. The cells were grown, in acontrolled environment (37° C., 5% CO₂), as monolayers in Dulbecco'smodified Eagle's Medium (GIBCO, Grand Island, N.Y.) containing 25 mMglucose and supplemented with 10% bovine calf serum, 100 units/mlpenicillin g, and 100 μg/ml streptomycin sulfate. Stable clones werethen selected for resistance to the antibiotic G-418 (1 mg/ml), andmembranes were harvested and assayed for their ability to bind[³H]prazosin as described below (see “Radioligand Binding assays”).

[0342] The cell line expressing the human α_(1d) receptor used hereinwas designated L-α_(1A) (old nomenclature) and was deposited with theAmerican Type Culture Collection, 12301 Parklawn Drive, Rockville, Md.20852, U.S.A. under the provisions of the Budapest Treaty for theInternational Recognition of the Deposit of Microorganisms for thePurposes of Patent Procedure. The cell line expressing the human α_(1d)receptor, was accorded ATCC Accession No. CRL 11138, and was depositedon Sep. 25, 1992.

[0343] α_(1b) Human Adrenergic Receptor: The entire coding region ofα_(1b) (1563 bp), including 200 base pairs and 5′ untranslated sequence(5′ UT) and 600 bp of 3′ untranslated sequence (3′ UT), was cloned intothe EcoRI site of pCEXV-3 eukaryotic expression vector. The constructinvolved ligating the full-length containing EcoRI brainstem cDNAfragment from λ ZapII into the expression vector. Stable cell lines wereselected as described above. The cell line used herein was designatedL-U₁B and was deposited with the American Type Culture Collection, 12301Parklawn Drive, Rockville, Md. 20852, U.S.A. under the provisions of theBudapest Treaty for the International Recognition of the Deposit ofMicroorganisms for the Purposes of Patent Procedure. The cell lineL-α_(1B) was accorded ATCC Accession No. CR 11139, on Sep. 29, 1992.

[0344] α_(1a) Human Adrenergic Receptor: The entire coding region ofα_(1a) (1401 bp) , including 400 base pairs of 5′ untranslated sequence(5′ UT) and 200 bp of 3′ untranslated sequence (3′ UT), was cloned intothe KpnI site of the polylinker-modified pCEXV-3-derived eukaryoticexpression vector, EXJ.RH. The construct involved ligating three partialoverlapping fragments: a 5′ 0.6 kb HincII genomic clone, a central 1.8EcoRI hippocampal cDNA clone, and a 3′ 0.6Kb PstI genomic clone. Thehippocampal cDNA fragment overlaps with the 5′ and 3′ genomic clones sothat the HincII and PstI sites at the 5′ and 3′ ends of the cDNA clone,respectively, were utilized for ligation. This full-length clone wascloned into the KpnI site of the expression vector, using the 5′ and 3′KpnI sites of the fragment, derived from vector (i.e., pBluescript) and39-untranslated sequences, respectively. Stable cell lines were selectedas described above. The stable cell line expressing the human α_(1a)receptor used herein was designated L-α_(1C) (old nomenclature) and wasdeposited with the American Type Culture Collection, 12301 ParklawnDrive, Rockville, Md. 20852, U.S.A. under the provisions of the BudapestTreaty for the International Recognition of the Deposit ofMicroorganisms for the Purposes of Patent Procedure. The cell lineexpressing the human a,, receptor was accorded Accession No. CR 11140,on Sep. 25, 1992.

[0345] Radioligand Binding Assays for α₁ receptors:

[0346]

[0347] Transfected cells from culture flasks were scraped into 5 ml of 5mM Tris-HCl, 5 mM EDTA, pH 7.5, and lysed by sonication. The celllysates were centrifuged at 1000 rpm for 5 min at 4° .C, and thesupernatant was centrifuged at 30,000×g for 20 min at 4° C. The pelletwas suspended in 50 mM Tris-HCl, 1 mM MgCl₂, and 0.1% ascorbic acid atpH 7.5. Binding of the a, antagonist [³H]prazosin (0.5 nM, specificactivity 76.2 Ci/mmol) to membrane preparations of LM(tk−) cells wasdone in a final volume of 0.25 ml and incubated at 37° C. for 20 min.Nonspecific binding was determined in the presence of 10 μgphentolamine. The reaction was stopped by filtration through GF/Bfilters using a cell harvester. Inhibition experiments, routinelyconsisting of 7 concentrations of the tested compounds, were analyzedusing a non-linear regression curve-fitting computer program to obtainKi values.

[0348] α₂ Human Adrenergic Receptors: To determine the potency of α₂antagonists at the α₂ receptors, LM(tk−) cell lines stably transfectedwith the genes encoding the α_(2a), α_(2b), and α_(2c) receptors wereused. The cell line expressing the α_(2a) receptor is designatedL-α_(2A), and was deposited on Nov. 6, 1992 under ATCC Accession No. CRL11180. The cell line expressing the α_(2b) receptor is designatedL—NGC-α_(2B), and was deposited on Oct. 25, 1989 under ATCC AccessionNo. CRL10275. The cell line expressing the α_(2c) receptor is designatedL-α_(2C), and was deposited on Nov. 6, 1992 under ATCC Accession No.CRL-11181. All the cell lines were deposited with the American TypeCulture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A.under the provisions of the Budapest Treaty for the InternationalRecognition of the Deposit of Microorganisms for the Purposes of PatentProcedure. Cell lysates were prepared as described above (seeRadioligand Binding Assays), and suspended in 25 mM glycylglycine buffer(pH 7.6 at room temperature). Equilibrium competition binding assay wereperformed using [3H]rauwolscine (0.5nM), and nonspecific binding wasdetermined by incubation with 10 μM phentolamine. The bound radioligandwas separated by filtration through GF/B filters using a cell harvester.

[0349] Determination of the Activity of α₁ Antagonists at CalciumChannels:

[0350] The potency of α₁ antagonists at calcium channels may bedetermined in competition binding assays of [3H]nitrendipine to membranefragments of rat cardiac muscle, essentially as described by Glossmanand Ferry (Methods in Enzymology 109:513-550, 1985). Briefly, the tissueis minced and homogenized in 50 mM Tris-HCl (pH 7.4) containing 0.1 mMphenylmethylsulfonyl fluoride. The homogenates are centrifuged at 1000 gfor 15 minutes, and the resulting supernatant centrifuged at 45,000 gfor 15 minutes. The 45,000 g pellet is suspended in buffer andcentrifuged a second time. Aliquots of membrane protein are thenincubated for 30 minutes at 37° C. in the presence of [3H]nitrendipine(1 nM), and nonspecific binding determined in the presence of 10 μgnifedipine. The bound radioligand is separated by filtration throughGF/B filters using a cell harvester.

[0351] The compounds described above were assayed using cloned humanalpha adrenergic receptors. The preferred compounds were found to beselective α_(1a) antagonists. The binding affinities of severalcompounds are illustrated in the following table.

[0352] Binding affinities of selected compounds of the present inventionat cloned human α_(1d), α_(1b) and α_(1a) receptors. (h=human) hα_(1d)hα_(1b) hα_(1a) Compound K_(i) (nM) K_(i) (nM) K_(i) (nM) 1 306.7 243.61.6 4 3162.3 3630.8 32.0 7 204.2 245.5 12.6 14 4200.8 1456.6 2.6 17579.9 464.2 3.8

[0353]

What is claimed is:
 1. A compound having the structure

where W is O, S, or NR₈; wherein R₈ is independently H, straight chainedor branched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl; where Y isindependently O or S; where R₂ is aryl or heteroaryl; wherein the arylor heteroaryl may be substituted with one or more of F; Cl; Br; I; —CN;—NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; and wherein n independently isan integer from 0 to 7 inclusive; where R₃ is independently H; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;where R₄ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y) R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl,or phenyl or benzyl; wherein the phenyl or benzyl may be substitutedwith one or more of F; Cl; Br; I; —CN; —NO₂; —N (R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl; and wherein t independently is an integer from 1 to 4inclusive; where R₅ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, orphenyl or benzyl; wherein the phenyl or benzyl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl,aminoalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; where R₆ isH, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, (CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl,or phenyl or benzyl; wherein the phenyl or benzyl may be substitutedwith one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl; where R₇ is H, —(CH₂)_(n)YR₈, —(CH₂)_(n)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₉, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, orphenyl or benzyl; wherein the phenyl or benzyl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(t)YR₈; —(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl,aminoalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; where q isan integer from 0 to 4 inclusive; where each R₈, n, and t independentlyis as defined above; where R₁ is

wherein each R₉ is H; straight chained or branched C₁-C₇ alkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C₅-C₇cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl maybe substituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl, orpolyfluorocycloalkyl; or C₅-C₇ cycloalkenyl; wherein each R₁₀ is H; F;—OH; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; aryl or heteroaryl; straightchained or branched C₁-C₇ alkyl, hydroxyalkyl, aminoalkyl,carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, or polyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;wherein the alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may besubstituted with one or more aryl or heteroaryl; wherein the aryl orheteroaryl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl, orpolyfluorocycloalkyl; or C₅-C₇ cycloalkenyl; wherein each R₁₁ isindependently H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇cycloalkenyl; wherein each R₁₂ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y) R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇ alkyl, straightchained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇cycloalkenyl; wherein R₁₃ is H, C₁-C₇ alkyl, —C(O)R₂, aryl, heteroaryl,C₁-C₇ alkyl substituted with one or two aryl, or C₁-C₇ alkyl substitutedwith one or two heteroaryl; wherein the aryl or heteroaryl may besubstituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl; straight chainedor branched C₂-C₇ aminoalkyl, alkenyl, or alkynyl; C₃-C₇ cycloalkyl; orC₅-C₇ cycloalkenyl; wherein R₁₄ is H, straight chained or branched C₁-C₇akyl; wherein Z is O, S, NR₁₄, CO, CH₂,

wherein Y₁, Y₂, and Y₃ independently are H; F; Cl; Br; I; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; wherein each m is independently 1 or 2; whereineach p is independently an integer from 0 to 2 inclusive; wherein J is

or C₂-C₇ alkenyl; wherein each R₁₅ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)CO₂R₈, —(CH₂)_(t)N(R₈)₂,—(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straight chained or branchedC₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl,C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl; wherein each R₁₆ isindependently H, —(CH₂)_(t)YR₈, (CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂) N (R8) 2, —(CH₂)CN, straight chained or branchedC₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl,C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl; wherein each R₁₇ isindependently H; F; —(CH₂)_(t)YR₈; —(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈; —(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; —C(Y)R₈;—C(Y)N(R₈)₂; —CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; wherein each R₁₈ is independently H; F;—(CH₂)_(t)YR₈; —(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; wherein L is S, O, or N(R₈);wherein u is an integer from 0 to 1 inclusive; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein thecompound comprises the (+) enantiomer.
 3. The compound of claim 1,wherein the compound comprises the (−) enantiomer.
 4. The compound ofclaim 1, wherein W is O.
 5. The compound of claim 1, wherein J is


6. The compound of claim 5, wherein R₁ is


7. The compound of claim 6, wherein R₉ is aryl or heteroaryl, whereinthe aryl or heteroaryl may be substituted with one or more of F; Cl; Br;I; —(CH₂)_(n)YR₈ ; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N (R₈)₂; —SO₂R₈; straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl; and whereinR₁₀ is H; —ON; —OH; —CO₂R₈; aryl or heteroaryl; wherein the aryl orheteroaryl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; (CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—ON; —NO₂; —N(R₈)₂; —SO₂R₉; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl.
 8. The compound of claim 7 havingthe structure:

wherein R₂ is phenyl; wherein the phenyl may be substituted with one ormore of F; Cl; Br; I; —CN; —NO₂; —N (R₈)₂; —SO₂R₈; (CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)CO₂R₈; straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl.
 9. Thecompound of claim 8 wherein J is


10. The compound of claim 9 wherein R₁ is


11. The compound of claim 10, wherein R₉ is phenyl or pyridyl, whereinthe phenyl or pyridyl may be substituted with one or more of F; Cl; Br;I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂;(CH₂)_(n)CO₂R₈; —ON; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl; wherein R₁₀ is H, —ON,—OH, —CO₂R₈, or phenyl; wherein the phenyl may be substituted with oneor more of F; Cl; Br; I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈, —CN; —NO₂; —N(R₈)₂; —SO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, orpolyfluoroalkyl; and wherein R₁₃ is phenyl; wherein the phenyl may besubstituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl; straight chainedor branched C₂-C₇ aminoalkyl, alkenyl, or alkynyl; C₃-C₇ cycloalkyl; orC₅-C₇ cycloalkenyl.
 12. A pharmaceutical composition comprising atherapeutically effective amount of the compound of claim 1 and apharmaceutically acceptable carrier.
 13. The pharmaceutical compositionof claim 12, wherein the amount of the compound is an amount from about0.01 mg to about 800 mg.
 14. The pharmaceutical composition of claim 13,wherein the amount of the compound is from about 0.01 mg to about 500mg.
 15. The pharmaceutical composition of claim 14, wherein the amountof the compound is from about 0.01 mg to about 250 mg.
 16. Thepharmaceutical composition of claim 15, wherein the amount of thecompound is from about 0.1 mg to about 60 mg.
 17. The pharmaceuticalcomposition of claim 16, wherein the amount of the compound is fromabout 1 mg to about 20 mg.
 18. The pharmaceutical composition of claim12, wherein the carrier is a liquid and the composition is a solution.19. The pharmaceutical composition of claim 12, wherein the carrier is asolid and the composition is a tablet.
 20. The pharmaceuticalcomposition of claim 12, wherein the carrier is a gel and thecomposition is a suppository.
 21. The pharmaceutical composition ofclaim 12, wherein the compound additionally does not cause a fall inblood pressure at dosages effective to alleviate benign prostatichyperplasia.
 22. A method of treating a subject suffering from benignprostatic hyperplasia which comprises administering to the subject anamount of the compound of claim 1 effective to treat benign prostatichyperplasia.
 23. A method of claim 22, wherein the compound additionallydoes not cause a fall in blood pressure at dosages effective toalleviate benign prostatic hyperplasia.
 24. The method of claim 23,wherein the compound effects treatment of benign prostatic hyperplasiaby relaxing lower urinary tract tissue.
 25. The method of claim 24,wherein lower urinary tract tissue is prostatic smooth muscle.
 26. Amethod of treating a subject suffering from high intraocular pressurewhich comprises administering to the subject an amount of the compoundof claim 1 effective to lower intraocular pressure.
 27. A method oftreating a subject suffering from a disorder associated with highcholesterol which comprises administering to the subject an amount ofthe compound of claim 1 effective to inhibit cholesterol synthesis. 28.A method of treating a subject suffering from cardiac arrhythmia whichcomprises administering to the subject an amount of the compound ofclaim 1 effective to treat cardiac arrhythmia.
 29. A method of treatinga subject suffering from impotency which comprises administering to thesubject an amount of the compound of claim 1 effective to treatimpotency.
 30. A method of treating a subject suffering fromsympathetically mediated pain which comprises administering to thesubject an amount of the compound of claim 1 effective to treatsympathetically mediated pain.
 31. A method of treating a subjectsuffering from migraine which comprises administering to the subject anamount of the compound of claim 1 effective to treat migraine.
 32. Amethod of treating a disease which is susceptible to treatment byantagonism of the α_(1a) receptor which comprises administering to thesubject an amount of the compound of claim 1 effective to treat thedisease.
 33. A method of treating a subject suffering from benignprostatic hyperplasia which comprises administering to the subject anamount of the compound of claim 1 in combination with a 5- alphareductase inhibitor effective to treat benign prostatic hyperplasia. 34.The method of claim 33, wherein the 5-alpha reductase inhibitor isfinasteride.
 35. A pharmaceutical composition comprising atherapeutically effective amount of the compound of claim 1 incombination with a therapeutically effective amount of finasteride and apharmaceutically acceptable carrier.
 36. The pharmaceutical compositionof claim 35, wherein the compound is present in an amount from about0.01 mg to about 800 mg and the therapeutically effective amount of thefinasteride is about 5 mg.
 37. The pharmaceutical composition of claim36, wherein the compound is present in an amount from about 0.1 mg toabout 60 mg and the therapeutically effective amount of finasteride isabout 5 mg.
 38. The pharmaceutical composition of claim 37, wherein thecompound is present in an amount from about 1 mg to about 20 mg and thetherapeutically effective amount of finasteride is about 5 mg.
 39. Amethod of relaxing lower urinary tract tissue which comprises contactingthe lower urinary tract tissue with an amount of the compound of claim 1effective to relax lower urinary tract tissue.
 40. The method of claim39, wherein the lower urinary tract tissue is prostatic smooth muscle.41. A method of relaxing lower urinary tract tissue in a subject whichcomprises administering to the subject an amount of the compound ofclaim 1 effective to relax lower urinary tract tissue.
 42. The method ofclaim 41, wherein the lower urinary tract tissue is prostatic smoothmuscle.
 43. A pharmaceutical composition made by combining atherapeutically effective amount of the compound of claim 1 and apharmaceutically acceptable carrier.
 44. A pharmaceutical compositionmade by combining a therapeutically effective amount of the compound ofclaim 1 with a therapeutically effective amount of finasteride and apharmaceutically acceptable carrier.
 45. A process for making apharmaceutical composition comprising combining a therapeuticallyeffective amount of the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 46. A process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofthe compound of claim 1 with a therapeutically effective amount offinasteride and a pharmaceutically acceptable carrier.